Heterocyclic modulators of nuclear receptors

ABSTRACT

Compounds, compositions and methods for modulating the activity of nuclear receptors are provided. In particular, heterocyclic compounds are provided for modulating the activity of farnesoid X receptor (FXR), liver X receptor (LXR) and/or orphan nuclear receptors. In certain embodiments, the compounds are thiazolidinone derivatives.

RELATED APPLICATION

Benefit of priority under 35 U.S.C. 119(e) is claimed herein to U.S.provisional patent application No. 60/342,720, filed Dec. 21, 2001, toMartin et al., entitled “HETEROCYCLIC MODULATORS OF NUCLEAR RECEPTORS.”The disclosure of the above-referenced application is incorporated byreference herein in its entirety.

FIELD

Compounds, compositions and methods for modulating the activity ofnuclear receptors are provided. In particular, heterocyclic compoundsare provided for modulating the activity of orphan nuclear receptors.

BACKGROUND Nuclear Receptors

Nuclear receptors are a superfamily of regulatory proteins that arestructurally and functionally related and are receptors for, e.g.,steroids, retinoids, vitamin D and thyroid hormones (see, e.g., Evans(1988) Science 240:889-895). These proteins bind to cis-acting elementsin the promoters of their target genes and modulate gene expression inresponse to ligands for the receptors.

Nuclear receptors can be classified based on their DNA bindingproperties (see, e.g., Evans, supra and Glass (1994) Endocr. Rev.15:391-407). For example, one class of nuclear receptors includes theglucocorticoid, estrogen, androgen, progestin and mineralocorticoidreceptors which bind as homodimers to hormone response elements (HREs)organized as inverted repeats (see, e.g., Glass, supra). A second classof receptors, including those activated by retinoic acid, thyroidhormone, vitamin D₃, fatty acids/peroxisome proliferators (i.e.,peroxisome proliferator activated receptor (PPAR)) and ecdysone, bind toHREs as heterodimers with a common partner, the retinoid X receptors(i.e., RXRs, also known as the 9-cis retinoic acid receptors; see, e.g.,Levin et al. (1992) Nature 355:359-361 and Heyman et al. (1992) Cell68:397-406).

RXRs are unique among the nuclear receptors in that they bind DNA as ahomodimer and are required as a heterodimeric partner for a number ofadditional nuclear receptors to bind DNA (see, e.g., Mangelsdorf et al.(1995) Cell 83:841-850). The latter receptors, termed the class IInuclear receptor subfamily, include many which are established orimplicated as important regulators of gene expression. There are threeRXR genes (see, e.g., Mangelsdorf et al. (1992) Genes Dev. 6:329-344),coding for RXRα, -β, and -γ, all of which are able to heterodimerizewith any of the class II receptors, although there appear to bepreferences for distinct RXR subtypes by partner receptors in vivo (see,e.g., Chiba et al. (1997) Mol. Cell. Biol. 17:3013-3020). In the adultliver, RXRα is the most abundant of the three RXRs (see, e.g.,Mangelsdorf et al. (1992) Genes Dev. 6:329-344), suggesting that itmight have a prominent role in hepatic functions that involve regulationby class II nuclear receptors. See also, Wan et al. (2000) Mol. Cell.Biol. 20:4436-4444.

Orphan Nuclear Receptors

Included in the nuclear receptor superfamily of regulatory proteins arenuclear receptors for whom the ligand is known and those which lackknown ligands. Nuclear receptors falling in the latter category arereferred to as orphan nuclear receptors. The search for activators fororphan receptors has led to the discovery of previously unknownsignaling pathways (see, e.g., Levin et al., (1992), supra and Heyman etal., (1992), supra). For example, it has been reported that bile acids,which are involved in physiological processes such as cholesterolcatabolism, are ligands for FXR (infra).

Since it is known that products of intermediary metabolism act astranscriptional regulators in bacteria and yeast, such molecules mayserve similar functions in higher organisms (see, e.g., Tomkins (1975)Science 189:760-763 and O'Malley (1989) Endocrinology 125:1119-1120).For example, one biosynthetic pathway in higher eukaryotes is themevalonate pathway, which leads to the synthesis of cholesterol, bileacids, porphyrin, dolichol, ubiquinone, carotenoids, retinoids, vitaminD, steroid hormones and farnesylated proteins.

FXR

FXR (originally isolated as RIP14 (retinoid X receptor-interactingprotein-14), see, e.g., Seol et al. (1995) Mol. Endocrinol. 9:72-85) isa member of the nuclear hormone receptor superfamily and is primarilyexpressed in the liver, kidney and intestine (see, e.g., Seol et al.,supra and Forman et al. (1995) Cell 81:687-693). It functions as aheterodimer with the retinoid X receptor (RXR) and binds to responseelements in the promoters of target genes to regulate genetranscription. The FXR-RXR heterodimer binds with highest affinity to aninverted repeat-1 (IR-1) response element, in which consensusreceptor-binding hexamers are separated by one nucleotide. FXR is partof an interrelated process, in that FXR is activated by bile acids (theend product of cholesterol metabolism) (see, e.g., Makishima et al.(1999) Science 284:1362-1365, Parks et al. (1999) Science 284:1365-1368,Wang et al. (1999) Mol. Cell. 3:543-553), which serve to inhibitcholesterol catabolism. See also, Urizar et al. (2000) J. Biol. Chem.275:39313-39317.

LXRα and LXRβ

LXRα is found predominantly in the liver, with lower levels found inkidney, intestine, spleen and adrenal tissue (see, e.g., Willy, et al.(1995) Gene Dev. 9(9):1033-1045). LXRβ, also known as UR (ubiquitousreceptor), is ubiquitous in mammals and was found in nearly all tissuesexamined. LXRs are activated by certain naturally occurring, oxidizedderivatives of cholesterol (see, e.g., Lehmann, et al. (1997) J. Biol.Chem. 272(6):3137-3140). LXRα is activated by oxycholesterol andpromotes cholesterol metabolism (Peet et al. (1998) Cell 93:693-704).Thus, LXRs appear to play a role in, e.g., cholesterol metabolism (see,e.g., Janowski, et al. (1996) Nature 383:728-731).

Nuclear Receptors and Disease

Nuclear receptor activity has been implicated in a variety of diseasesand disorders, including, but not limited to, hypercholesterolemia (see,e.g., International Patent Application Publication No. WO 00/57915),osteoporosis and vitamin deficiency (see, e.g., U.S. Pat. No.6,316,5103), hyperlipoproteinemia (see, e.g., International PatentApplication Publication No. WO 01/60818), hypertriglyceridemia,lipodystrophy, peripheral occlusive disease, ischemic stroke,hyperglycemia and diabetes mellitus (see, e.g., International PatentApplication Publication No. WO 01/82917), atherosclerosis and gallstones(see, e.g., International Patent Application Publication No. WO00/37077), disorders of the skin and mucous membranes (see, e.g., U.S.Pat. Nos. 6,184,215 and 6,187,814, and International Patent ApplicationPublication No. WO 98/32444), acne (see, e.g., International PatentApplication Publication No. WO 00/49992), and cancer, Parkinson'sdisease and Alzheimer's disease (see, e.g., International PatentApplication Publication No. WO 00/17334). Activity of nuclear receptors,including FXR, LXRs and/or orphan nuclear receptors, has been implicatedin physiological processes including, but not limited to, bile acidbiosynthesis, cholesterol metabolism or catabolism, and modulation ofcholesterol 7α-hydroxylase gene (CYP7A1) transcription (see, e.g.,Chiang et al. (2000) J. Biol. Chem. 275:10918-10924), HDL metabolism(see, e.g., Urizar et al. (2000) J. Biol. Chem. 275:39313-39317),hyperlipidemia, cholestasis, and increased cholesterol efflux andincreased expression of ATP binding cassette transporter protein (ABC1)(see, e.g., International Patent Application Publication No. WO00/78972).

Thus, there is a need for compounds, compositions and methods ofmodulating the activity of nuclear receptors, including FXR, LXRs and/ororphan nuclear receptors. Such compounds are useful in the treatment,prevention, or amelioration of one or more symptoms of diseases ordisorders in which nuclear receptor activity is implicated.

SUMMARY

Compounds for use in compositions and methods for modulating theactivity of nuclear receptors are provided. In particular, compounds foruse in compositions and methods for modulating farnesoid X receptor(FXR), liver X receptors (LXRα and LXRβ) and/or orphan nuclearreceptors, are provided. In certain embodiments, the compounds areheterocyclic compounds that are substituted with a heterocyclylene groupand an imine moiety. In one embodiment, the compounds provided hereinare agonists of FXR and/or LXR. In another embodiment, the compoundsprovided herein are antagonists of FXR and/or LXR. Agonists that exhibitlow efficacy are, in certain embodiments, antagonists.

In one embodiment, the compounds for use in the compositions and methodsprovided herein have formulae I:

or a pharmaceutically acceptable derivative thereof, where A, D, E and Gare selected from (i) or (ii) as follows:

(i) A and G are each independently selected from hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaralkyl, substituted or unsubstitutedheteroarylium, substituted or unsubstituted heteroaryliumalkyl, halo,pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³, or Aand G together form substituted or unsubstituted alkylene, substitutedor unsubstituted azaalkylene, substituted or unsubstituted oxaalkylene,substituted or unsubstituted thiaalkylene, substituted or unsubstitutedalkenylene, substituted or unsubstituted alkynylene, substituted orunsubstituted 1,3-butadienylene, substituted or unsubstituted1-aza-1,3-butadienylene, or substituted or unsubstituted2-aza-1,3-butadienylene;

 D and E are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo and pseudohalo or D and E togetherform a bond; or

(ii) A and D; or E and G; together form substituted or unsubstitutedalkylene, substituted or unsubstituted azaalkylene, substituted orunsubstituted oxaalkylene, or substituted or unsubstituted thiaalkylene;and the others of A, D, E and G are selected as in (i);

X¹ and X² are each independently selected from O, S, S(═O), S(═O)₂, Se,NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ and R² are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; where

R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo,OR¹⁰, NR¹⁴R¹⁵ and C(═J)R¹³;

R¹⁰, R¹¹ and R¹² are each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl or C(═J)R¹³;

J is O, S or NR¹⁴;

R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵;

R¹⁴, R¹⁵ and R¹⁶ are each independently selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl;

where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylium,aralkyl, heteroaralkyl and heteroaryliumalkyl moieties of A, D, E, G,R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstitutedor substituted with one or more substituents, in one embodiment one tothree or four substituents, each independently selected from Q¹, whereQ¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl,mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl,polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy,aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo,arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)—O—)or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is 1 or2; or two Q¹ groups, which substitute the same atom, together formalkylene; and

each Q¹ is independently unsubstituted or substituted with one or moresubstituents, in one embodiment one, two or three substituents, eachindependently selected from Q²;

each Q² is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile,nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl,haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy,aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—)or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is 1or 2; or two Q² groups, which substitute the same atom, together formalkylene;

each Q² is independently unsubstituted or substituted with one or more,in one embodiment one, two or three, substituents each independentlyselected from alkyl, halo and pseudohalo;

R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, arylor —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene;

R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl;

R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl or heterocyclylalkyl; and

R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹.

In another embodiment, the compounds for use in the compositions andmethods provided herein have formulae I:

or a pharmaceutically acceptable derivative thereof, where A, D, E and Gare selected from (i) or (ii) as follows:

(i) A and G are each independently selected from hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaralkyl, substituted or unsubstitutedheteroarylium, substituted or unsubstituted heteroaryliumalkyl, halo,pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³, or Aand G together form substituted or unsubstituted alkylene, substitutedor unsubstituted azaalkylene, substituted or unsubstituted oxaalkylene,substituted or unsubstituted thiaalkylene, substituted or unsubstitutedalkenylene, substituted or unsubstituted alkynylene, substituted orunsubstituted 1,3-butadienylene, substituted or unsubstituted1-aza-1,3-butadienylene, or substituted or unsubstituted2-aza-1,3-butadienylene;

 D and E are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo and pseudohalo or D and E togetherform a bond; or

(ii) A and D; or E and G; together form substituted or unsubstitutedalkylene, substituted or unsubstituted azaalkylene, substituted orunsubstituted oxaalkylene, or substituted or unsubstituted thiaalkylene;and the others of A, D, E and G are selected as in (i);

X¹ and X² are each independently selected from O, S, S(═O), S(═O)₂, Se,NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ and R² are eachindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; where

R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo,OR¹⁰, NR¹⁴R¹⁵ and C(═J)R¹³;

R¹⁰, R¹¹ and R¹² are each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl or C(═J)R¹³;

J is O, S or NR¹⁴;

R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵;

R¹⁴, R¹⁵ and R¹⁶ are each independently selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl;

where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylium,aralkyl, heteroaralkyl and heteroaryliumalkyl moieties of A, D, E, G,R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstitutedor substituted with one or more substituents, in one embodiment one tothree or four substituents, each independently selected from Q¹, whereQ¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl,mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl,polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy,aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkyl phosphonyl, alkylarylphosphonyl,diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio,perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano,alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy,hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy,alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy,diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl,alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl,alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or twoQ¹ groups, which substitute atoms in a 1,2 or 1,3 arrangement, togetherform alkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—)or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is 1or 2; or two Q¹ groups, which substitute the same atom, together formalkylene; and

each Q¹ is independently unsubstituted or substituted with one or moresubstituents, in one embodiment one, two or three substituents, eachindependently selected from Q²;

each Q² is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile,nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl,haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy,aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R¹⁵)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—)or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is 1or 2; or two Q² groups, which substitute the same atom, together formalkylene;

R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, arylor —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene;

R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl;

R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl or heterocyclylalkyl; and

R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹.

In certain embodiments herein, the compounds are selected with theproviso that when R³ is substituted or unsubstituted heteroarylium thenthe heteroatom substituent is not alkyl or aryl. In another embodiment,the compounds are selected with the proviso that R³ is not substitutedor unsubstituted heteroarylium or substituted or unsubstitutedheteroaryliumalkyl. In other embodiments, the compounds are selectedwith the proviso that R³ is not heteroaryl. In further embodiments, thecompounds are selected with the proviso that R³ is not alkyl. In anotherembodiment, the compounds are selected with the proviso that R³ is notheterocycloaryl (i.e., an aryl group possessing a fused heterocyclicmoiety).

The groups A, D, E, G, X¹, X², X³, R¹, R² and R³ are selected such thatthe resulting compound has nuclear receptor modulation activity, such asin at least one assay described herein, such as FXR antagonist oragonist activity, and, in certain embodiments, at an IC₅₀ or EC₅₀ ofless than about 100 μM. The FXR IC₅₀ or EC₅₀ values for the compoundsprovided herein are, in certain embodiments, less than about 50 μM, 25μM, 10 μM, 1 μM, 100 nM, 10 nM or 1 nM.

Also of interest are any pharmaceutically-acceptable derivatives,including salts, esters, enol ethers, enol esters, solvates, hydratesand prodrugs of the compounds described herein.Pharmaceutically-acceptable salts, include, but are not limited to,amine salts, such as but not limited to N,N′-dibenzylethylenediamine,chloroprocaine, choline, ammonia, diethanolamine and otherhydroxyalkylamines, ethylenediamine, N-methylglucamine, procaine,N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethylbenzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc, aluminum, and other metal salts, such as but not limited tosodium hydrogen phosphate and disodium phosphate; and also including,but not limited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates and fumarates.

Pharmaceutical compositions formulated for administration by anappropriate route and means containing effective concentrations of oneor more of the compounds provided herein, or pharmaceutically acceptablederivatives thereof, that deliver amounts effective for the treatment,prevention, or amelioration of one or more symptoms of diseases ordisorders that are modulated or otherwise affected by nuclear receptoractivity, including FXR, LXR and/or orphan nuclear receptor activity, orin which nuclear receptor activity, including FXR, LXR and/or orphannuclear receptor activity, is implicated, are also provided. Theeffective amounts and concentrations are effective for ameliorating anyof the symptoms of any of the diseases or disorders.

Methods for treatment, prevention, or amelioration of one or moresymptoms of diseases or disorders mediated by or in which nuclearreceptor activity, including FXR, LXR and/or orphan nuclear receptoractivity, is implicated, are provided. Such methods include methods oftreatment, prevention and amelioration of one or more symptoms ofhypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia,lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia,atherosclerosis, gallstone disease, acne vulgaris, acneiform skinconditions, diabetes, Parkinson's disease, cancer, Alzheimer's disease,inflammation, immunological disorders, lipid disorders, obesity,conditions characterized by a perturbed epidermal barrier function,hyperlipidemia, cholestasis, peripheral occlusive disease, ischemicstroke, conditions of disturbed differentiation or excess proliferationof the epidermis or mucous membrane, or cardiovascular disorders, usingone or more of the compounds provided herein, or pharmaceuticallyacceptable derivatives thereof.

Methods of modulating the activity of nuclear receptors, including FXR,LXR and/or-orphan nuclear receptors, using the compounds andcompositions provided herein are also provided. The compounds andcompositions provided herein are active in assays that measure theactivity of nuclear receptors, including FXR, LXR and/or orphan nuclearreceptors, including the assays provided herein. These methods includeinhibiting and up-regulating the activity of nuclear receptors,including FXR, LXR and/or orphan nuclear receptors.

Methods of reducing cholesterol levels in a subject in need thereof byadministration of one or more compounds or compositions provided hereinare also provided.

Methods of modulating cholesterol metabolism using the compounds andcompositions provided herein are provided.

Methods of treating, preventing, or ameliorating one or more symptoms ofdiseases or disorders which are affected by cholesterol, triglyceride,or bile acid levels by administration of one or more of the compoundsand compositions provided herein are also provided.

In practicing the methods, effective amounts of the compounds orcompositions containing therapeutically effective concentrations of thecompounds, which are formulated for systemic delivery, includingparenteral, oral, or intravenous delivery, or for local or topicalapplication, for the treatment of nuclear receptor, including FXR, LXRand/or orphan nuclear receptor, mediated diseases or disorders, ordiseases or disorders in which nuclear receptor activity, including FXR,LXR and/or orphan nuclear receptor activity, is implicated, including,but not limited to, hypercholesterolemia, hyperlipoproteinemia,hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus,dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris,acneiform skin conditions, diabetes, Parkinson's disease, cancer,Alzheimer's disease, inflammation, immunological disorders, lipiddisorders, obesity, conditions characterized by a perturbed epidermalbarrier function, hyperlipidemia, cholestasis, peripheral occlusivedisease, ischemic stroke, conditions of disturbed differentiation orexcess proliferation of the epidermis or mucous membrane, orcardiovascular disorders, are administered to an individual exhibitingthe symptoms of these diseases or disorders. The amounts are effectiveto ameliorate or eliminate one or more symptoms of the diseases ordisorders.

Articles of manufacture containing packaging material, a compound orcomposition, or pharmaceutically acceptable derivative thereof, providedherein, which is effective for modulating the activity of nuclearreceptors, including FXR, LXR and/or orphan nuclear receptors, or fortreatment, prevention or amelioration of one or more symptoms of nuclearreceptor, including FXR, LXR and/or orphan nuclear receptor, mediateddiseases or disorders, or diseases or disorders in which nuclearreceptor activity, including FXR, LXR and/or orphan nuclear receptoractivity, is implicated, within the packaging material, and a label thatindicates that the compound or composition, or pharmaceuticallyacceptable derivative thereof, is used for modulating the activity ofnuclear receptors, including FXR, LXR and/or orphan nuclear receptors,or for treatment, prevention or amelioration of one or more symptoms ofnuclear receptor, including FXR, LXR and/or orphan nuclear receptor,mediated diseases or disorders, or diseases or disorders in whichnuclear receptor activity, including FXR, LXR and/or orphan nuclearreceptor activity, is implicated, are provided.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 provides in vitro data for the compounds whose synthesis isdescribed in the Examples. Average EC₅₀ (“EC50_AVG”) for FXR agonism isprovided as follows: A=0.0001-0.01 μM, B=0.01-0.1 μM, C=0.1-1.0 μM,D=1.0-10.0 μM and NC=not calculated or inactive. Average percentefficacy (“EFF_AVG”) for FXR agonism relative to control(chenodeoxycholic acid, CDCA) is provided as follows: A=>150%,B=100-150%, C=50-100%, D=0-50% and NC=not calculated or inactive.Average IC₅₀ (“IC50_AVG”) for FXR antagonism is provided as follows:A=0.0001-0.01 μM, B=0.01-0.1 μM, C=0.1-1.0 μM and D=1.0-10.0 μM. Averagepercent inhibition (“INHIB_AVG”) for FXR antagonism relative to control(chenodeoxycholic acid, CDCA) is provided as follows: E=>75%, F=50-75%,G=25-50%, H=0-25% and NEG=negative.

DETAILED DESCRIPTION OF EMBODIMENTS A. Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of ordinary skillin the art. All patents, applications, published applications and otherpublications are incorporated by reference in their entirety. In theevent that there are a plurality of definitions for a term herein, thosein this section prevail unless stated otherwise.

As used herein, a nuclear receptor is a member of a superfamily ofregulatory proteins that are receptors for, e.g., steroids, retinoids,vitamin D and thyroid hormones. These proteins bind to cis-actingelements in the promoters of their target genes and modulate geneexpression in response to a ligand therefor. Nuclear receptors may beclassified based on their DNA binding properties. For example, theglucocorticoid, estrogen, androgen, progestin and mineralocorticoidreceptors bind as homodimers to hormone response elements (HRES)organized as inverted repeats. Another example are receptors, includingthose activated by retinoic acid, thyroid hormone, vitamin D₃, fattyacids/peroxisome proliferators and ecdysone, that bind to HREs asheterodimers with a common partner, the retinoid X receptor (RXR). Amongthe latter receptors are FXR and LXR.

As used herein, an orphan nuclear receptor is a nuclear receptor forwhich the natural ligand is unknown.

As used herein, the term farnesoid X receptor or FXR refers to allmammalian forms of such receptor including, for example, alternativesplice isoforms and naturally occurring isoforms. Representative FXRspecies include, without limitation rat FXR (SEQ ID NO. 5), mouse FXR,and human FXR (SEQ ID NO. 7).

As used herein, liver X receptor or LXR or UR refers to a nuclearreceptor implicated in cholesterol homeostasis. As used herein, the termLXR refers to both LXRα and LXRβ, two forms of the protein found inmammals. Liver X receptor-α or LXRα refers to the receptor described inU.S. Pat. No. 5,757,661 and Willy et al. (1995) Gene Dev.9(9):1033-1045. Liver X receptor-β or LXRβ refers to the receptordescribed in Peet et al. (1998) Curr. Opin. Genet. Dev. 8(5):571-575;Song et al. (1995) Ann. N. Y. Acad. Sci. 761:38-49; Alberti et al.,(2000) Gene 243(1-2):93-103; and references cited therein.

As used herein, pharmaceutically acceptable derivatives of a compoundinclude salts, esters, enol ethers, enol esters, acetals, ketals,orthoesters, hemiacetals, hemiketals, acids, bases, solvates, hydratesor prodrugs thereof. Such derivatives may be readily prepared by thoseof skill in this art using known methods for such derivatization. Thecompounds produced may be administered to animals or humans withoutsubstantial toxic effects and either are pharmaceutically active or areprodrugs. Pharmaceutically acceptable salts include, but are not limitedto, amine salts, such as but not limited toN,N′-dibenzylethylenediamine, chloroprocaine, choline, ammonia,diethanolamine and other hydroxyalkylamines, ethylenediamine,N-methylglucamine, procaine, N-benzylphenethylamine,1-para-chlorobenzyl-2-pyrrolidin-1′-ylmethylbenzimidazole, diethylamineand other alkylamines, piperazine and tris(hydroxymethyl)aminomethane;alkali metal salts, such as but not limited to lithium, potassium andsodium; alkali earth metal salts, such as but not limited to barium,calcium and magnesium; transition metal salts, such as but not limitedto zinc; and other metal salts, such as but not limited to sodiumhydrogen phosphate and disodium phosphate; and also including, but notlimited to, salts of mineral acids, such as but not limited tohydrochlorides and sulfates; and salts of organic acids, such as but notlimited to acetates, lactates, malates, tartrates, citrates, ascorbates,succinates, butyrates, valerates and fumarates. Pharmaceuticallyacceptable esters include, but are not limited to, alkyl, alkenyl,alkynyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl andheterocyclyl esters of acidic groups, including, but not limited to,carboxylic acids, phosphoric acids, phosphinic acids, sulfonic acids,sulfinic acids and boronic acids. Pharmaceutically acceptable enolethers include, but are not limited to, derivatives of formula C═C(OR)where R is hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl,heteroaralkyl, cycloalkyl ar heterocyclyl. Pharmaceutically acceptableenol esters include, but are not limited to, derivatives of formulaC═C(OC(O)R) where R is hydrogen, alkyl, alkenyl, alkynyl, aryl,heteroaryl, aralkyl, heteroaralkyl, cycloalkyl ar heterocyclyl.Pharmaceutically acceptable solvates and hydrates are complexes of acompound with one or more solvent or water molecules, or 1 to about 100,or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.

As used herein, treatment means any manner in which one or more of thesymptoms of a disease or disorder are ameliorated or otherwisebeneficially altered. Treatment also encompasses any pharmaceutical useof the compositions herein, such as use for treating a nuclear receptor,including FXR, LXR and/or orphan nuclear receptor, mediated diseases ordisorders, or diseases or disorders in which nuclear receptor activity,including FXR, LXR and/or orphan nuclear receptor activity, isimplicated.

As used herein, amelioration of the symptoms of a particular disorder byadministration of a particular compound or pharmaceutical compositionrefers to any lessening, whether permanent or temporary, lasting ortransient that can be attributed to or associated with administration ofthe composition.

As used herein, the IC₅₀ refers to an amount, concentration or dosage ofa particular test compound that achieves a 50% inhibition of a maximalresponse, such as modulation of FXR activity, in an assay that measuressuch response.

As used herein, EC₅₀ refers to a dosage, concentration or amount of aparticular test compound that elicits a dose-dependent response at 50%of maximal expression of a particular response that is induced, provokedor potentiated by the particular test compound.

As used herein, a prodrug is a compound that, upon in vivoadministration, is metabolized by one or more steps or processes orotherwise converted to the biologically, pharmaceutically ortherapeutically active form of the compound. To produce a prodrug, thepharmaceutically active compound is modified such that the activecompound will be regenerated by metabolic processes. The prodrug may bedesigned to alter the metabolic stability or the transportcharacteristics of a drug, to mask side effects or toxicity, to improvethe flavor of a drug or to alter other characteristics or properties ofa drug. By virtue of knowledge of pharmacodynamic processes and drugmetabolism in vivo, those of skill in this art, once a pharmaceuticallyactive compound is known, can design prodrugs of the compound (see,e.g., Nogrady (1985) Medicinal Chemistry A Biochemical Approach, OxfordUniversity Press, New York, pages 388-392).

It is to be understood that the compounds provided herein may containchiral centers. Such chiral centers may be of either the (R) or (S)configuration, or may be a mixture thereof. Thus, the compounds providedherein may be enantiomerically pure, or be stereoisomeric ordiastereomeric mixtures. In the case of amino acid residues, suchresidues may be of either the L- or D-form. The configuration fornaturally occurring amino acid residues is generally L. When notspecified the residue is the L form. As used herein, the term “aminoacid” refers to α-amino acids which are racemic, or of either the D- orL-configuration. The designation “d” preceding an amino acid designation(e.g., dAla, dSer, dVal, etc.) refers to the D-isomer of the amino acid.The designation “dl” preceding an amino acid designation (e.g., dlPip)refers to a mixture of the L- and D-isomers of the amino acid. It is tobe understood that the chiral centers of the compounds provided hereinmay undergo epimerization in vivo. As such, one of skill in the art willrecognize that administration of a compound in its (R) form isequivalent, for compounds that undergo epimerization in vivo, toadministration of the compound in its (S) form.

As used herein, substantially pure means sufficiently homogeneous toappear free of readily detectable impurities as determined by standardmethods of analysis, such as thin layer chromatography (TLC), gelelectrophoresis, high performance liquid chromatography (HPLC) and massspectrometry (MS), used by those of skill in the art to assess suchpurity, or sufficiently pure such that further purification would notdetectably alter the physical and chemical properties, such as enzymaticand biological activities, of the substance. Methods for purification ofthe compounds to produce substantially chemically pure compounds areknown to those of skill in the art. A substantially chemically purecompound may, however, be a mixture of stereoisomers. In such instances,further purification might increase the specific activity of thecompound. The instant disclosure is meant to include all such possibleisomers, as well as, their racemic and optically pure forms. Opticallyactive (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques, such as reverse phase HPLC. When the compoundsdescribed herein contain olefinic double bonds or other centers ofgeometric asymmetry, and unless specified otherwise, it is intended thatthe compounds include both E and Z geometric isomers. Likewise, alltautomeric forms are also intended to be included.

As used herein, the nomenclature alkyl, alkoxy, carbonyl, etc. is usedas is generally understood by those of skill in this art.

As used herein, alkyl, alkenyl and alkynyl carbon chains, if notspecified, contain from 1 to 20 carbons, or 1 to 16 carbons, and arestraight or branched. Alkenyl carbon chains of from 2 to 20 carbons, incertain embodiments, contain 1 to 8 double bonds, and the alkenyl carbonchains of 2 to 16 carbons, in certain embodiments, contain 1 to 5 doublebonds. Alkynyl carbon chains of from 2 to 20 carbons, in certainembodiments, contain 1 to 8 triple bonds, and the alkynyl carbon chainsof 2 to 16 carbons, in certain embodiments, contain 1 to 5 triple bonds.Exemplary alkyl, alkenyl and alkynyl groups herein include, but are notlimited to, methyl, ethyl, propyl, isopropyl, isobutyl, n-butyl,sec-butyl, tert-butyl, isopentyl, neopentyl, tert-penytyl and isohexyl.As used herein, lower alkyl, lower alkenyl, and lower alkynyl refer tocarbon chains having from about 1 or about 2 carbons up to about 6carbons. As used herein, “alk(en)(yn)yl” refers to an alkyl groupcontaining at least one double bond and at least one triple bond.

As used herein, “cycloalkyl” refers to a saturated mono- or multicyclicring system, in certain embodiments of 3 to 10 carbon atoms, in otherembodiments of 3 to 6 carbon atoms; cycloalkenyl and cycloalkynyl referto mono- or multicyclic ring systems that respectively include at leastone double bond and at least one triple bond. Cycloalkenyl andcycloalkynyl groups may, in certain embodiments, contain 3 to 10 carbonatoms, with cycloalkenyl groups, in further embodiments, containing 4 to7 carbon atoms and cycloalkynyl groups, in further embodiments,containing 8 to 10 carbon atoms. The ring systems of the cycloalkyl,cycloalkenyl and cycloalkynyl groups may be composed of one ring or twoor more rings which may be joined together in a fused, bridged orspiro-connected fashion. “Cycloalk(en)(yn)yl” refers to a cycloalkylgroup containing at least one double bond and at least one triple bond.

As used herein, “substituted alkyl,” “substituted alkenyl,” “substitutedalkynyl,” “substituted cycloalkyl,” “substituted cycloalkenyl,” and“substituted cycloalkynyl” refer to alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl and cycloalkynyl groups, respectively, that are substitutedwith one or more substituents, in certain embodiments one to three orfour substituents, where the substituents are as defined herein,generally selected from Q¹.

As used herein, “aryl” refers to aromatic monocyclic or multicyclicgroups containing from 6 to 19 carbon atoms. Aryl groups include, butare not limited to groups such as fluorenyl, substituted fluorenyl,phenyl, substituted phenyl, naphthyl and substituted naphthyl.

As used herein, “heteroaryl” refers to a monocyclic or multicyclicaromatic ring system, in certain embodiments, of about 5 to about 15members where one or more, in one embodiment 1 to 3, of the atoms in thering system is a heteroatom, that is, an element other than carbon,including but not limited to, nitrogen, oxygen or sulfur. The heteroarylgroup may be optionally fused to a benzene ring. Heteroaryl groupsinclude, but are not limited to, furyl, imidazolyl, pyrrolidinyl,pyrimidinyl, tetrazolyl, thienyl, pyridyl, pyrrolyl, N-methylpyrrolyl,quinolinyl and isoquinolinyl.

As used herein, a “heteroarylium” group is a heteroaryl group that ispositively charged on one or more of the heteroatoms.

As used herein, “heterocyclyl” refers to a monocyclic or multicyclicnon-aromatic ring system, in one embodiment of 3 to 10 members, inanother embodiment of 4 to 7 members, in a further embodiment of 5 to 6members, where one or more, in certain embodiments, 1 to 3, of the atomsin the ring system is a heteroatom, that is, an element other thancarbon, including but not limited to, nitrogen, oxygen or sulfur. Inembodiments where the heteroatom(s) is(are) nitrogen, the nitrogen isoptionally substituted with alkyl, alkenyl, alkynyl, aryl, heteroaryl,aralkyl, heteroaralkyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, acyl, guanidino, or the nitrogen may be quaternizedto form an ammonium group where the substituents are selected as above.

As used herein, “substituted aryl,” “substituted heteroaryl” and“substituted heterocyclyl” refer to aryl, heteroaryl and heterocyclylgroups, respectively, that are substituted with one or moresubstituents, in certain embodiments one to three or four substituents,where the substituents are as defined herein, generally selected fromQ¹.

As used herein, “aralkyl” refers to an alkyl group in which one of thehydrogen atoms of the alkyl is replaced by an aryl group.

As used herein, “heteroaralkyl” refers to an alkyl group in which one ofthe hydrogen atoms of the alkyl is replaced by a heteroaryl group.

As used herein, “halo”, “halogen” or “halide” refers to F, Cl, Br or I.

As used herein, pseudohalides or pseudohalo groups are groups thatbehave substantially similar to halides. Such compounds can be used inthe same manner and treated in the same manner as halides. Pseudohalidesinclude, but are not limited to, cyanide, cyanate, thiocyanate,selenocyanate, trifluoromethoxy, and azide.

As used herein, “haloalkyl” refers to an alkyl group in which one ormore of the hydrogen atoms are replaced by halogen. Such groups include,but are not limited to, chloromethyl, trifluoromethyl and1-chloro-2-fluoroethyl.

As used herein, “haloalkoxy” refers to RO— in which R is a haloalkylgroup.

As used herein, “sulfinyl” or “thionyl” refers to —S(O)—. As usedherein, “sulfonyl” or “sulfuryl” refers to —S(O)₂—. As used herein,“sulfo” refers to —S(O)₂O—.

As used herein, “carboxy” refers to a divalent radical, —C(O)O—.

As used herein, “aminocarbonyl” refers to —C(O)NH₂.

As used herein, “alkylaminocarbonyl” refers to —C(O)NHR in which R isalkyl, including lower alkyl. As used herein, “dialkylaminocarbonyl”refers to —C(O)NR′R in which R′ and R are independently alkyl, includinglower alkyl; “carboxamide” refers to groups of formula —NRCOR in whichR′ and R are independently alkyl, including lower alkyl.

As used herein, “diarylaminocarbonyl” refers to —C(O)NRR′ in which R andR′ are independently selected from aryl, including lower aryl, such asphenyl.

As used herein, “arylalkylaminocarbonyl” refers to —C(O)NRR′ in whichone of R and R′ is aryl, including lower aryl, such as phenyl, and theother of R and R′ is alkyl, including lower alkyl.

As used herein, “arylaminocarbonyl” refers to —C(O)NHR in which R isaryl, including lower aryl, such as phenyl.

As used herein, “hydroxycarbonyl” refers to —COOH.

As used herein, “alkoxycarbonyl” refers to —C(O)OR in which R is alkyl,including lower alkyl.

As used herein, “aryloxycarbonyl” refers to —C(O)OR in which R is aryl,including lower aryl, such as phenyl.

As used herein, “alkoxy” and “alkylthio” refer to RO— and RS—, in whichR is alkyl, including lower alkyl.

As used herein, “aryloxy” and “arylthio” refer to RO— and RS—, in whichR is aryl, including lower aryl, such as phenyl.

As used herein, “alkylene” refers to a straight, branched or cyclic, incertain embodiments straight or branched, divalent aliphatic hydrocarbongroup, in one embodiment having from 1 to about 20 carbon atoms, inanother embodiment having from 1 to 12 carbons. In a further embodimentalkylene includes lower alkylene. There may be optionally inserted alongthe alkylene group one or more oxygen, sulfur, including S(═O) andS(═O)₂ groups, or substituted or unsubstituted nitrogen atoms, including—NR— and —N⁺RR— groups, where the nitrogen substituent(s) is(are) alkyl,aryl, aralkyl, heteroaryl, heteroaralkyl or COR′, where R′ is alkyl,aryl, aralkyl, heteroaryl, heteroaralkyl, —OY or —NYY, where Y ishydrogen, alkyl, aryl, heteroaryl, cycloalkyl or heterocyclyl. Alkylenegroups include, but are not limited to, methylene (—CH₂—), ethylene(—CH₂CH₂—), propylene (—(CH₂)₃—), methylenedioxy (—O—CH₂—O—) andethylenedioxy (—O—(CH₂)₂—O—). The term “lower alkylene” refers toalkylene groups having 1 to 6 carbons. In certain embodiments, alkylenegroups are lower alkylene, including alkylene of 1 to 3 carbon atoms.

As used herein, “azaalkylene” refers to —(CRR)_(n)—NR—(CRR)_(m)—, wheren and m are each independently an integer from 0 to 4. As used herein,“oxaalkylene” refers to —(CRR)_(n)—O—(CRR)_(m)—, where n and m are eachindependently an integer from 0 to 4. As used herein, “thiaalkylene”refers to —(CRR)_(n)—S—(CRR)_(m)—, —(CRR)_(n)—S(═O)—(CRR)_(m)—, and—(CRR)_(n)—S(═O)₂—(CRR)_(m)—, where n and m are each independently aninteger from 0 to 4. In certain embodiments herein, the “R” groups inthe definitions of azaalkylene, oxaalkylene and thiaalkylene are eachindependently selected from hydrogen and Q¹, as defined herein.

As used herein, “alkenylene” refers to a straight, branched or cyclic,in one embodiment straight or branched, divalent aliphatic hydrocarbongroup, in certain embodiments having from 2 to about 20 carbon atoms andat least one double bond, in other embodiments 1 to 12 carbons. Infurther embodiments, alkenylene groups include lower alkenylene. Theremay be optionally inserted along the alkenylene group one or moreoxygen, sulfur or substituted or unsubstituted nitrogen atoms, where thenitrogen substituent is alkyl. Alkenylene groups include, but are notlimited to, —CH═CH—CH═CH— and —CH═CH—CH₂—. The term “lower alkenylene”refers to alkenylene groups having 2 to 6 carbons. In certainembodiments, alkenylene groups are lower alkenylene, includingalkenylene of 3 to 4 carbon atoms.

As used herein, “alkynylene” refers to a straight, branched or cyclic,in certain embodiments straight or branched, divalent aliphatichydrocarbon group, in one embodiment having from 2 to about 20 carbonatoms and at least one triple bond, in another embodiment 1 to 12carbons. In a further embodiment, alkynylene includes lower alkynylene.There may be optionally inserted along the alkynylene group one or moreoxygen, sulfur or substituted or unsubstituted nitrogen atoms, where thenitrogen substituent is alkyl. Alkynylene groups include, but are notlimited to, —C≡C—C≡C—, —C≡C— and —C≡C—CH₂—. The term “lower alkynylene”refers to alkynylene groups having 2 to 6 carbons. In certainembodiments, alkynylene groups are lower alkynylene, includingalkynylene of 3 to 4 carbon atoms.

As used herein, “alk(en)(yn)ylene” refers to a straight, branched orcyclic, in certain embodiments straight or branched, divalent aliphatichydrocarbon group, in one embodiment having from 2 to about 20 carbonatoms and at least one triple bond, and at least one double bond; inanother embodiment 1 to 12 carbons. In further embodiments,alk(en)(yn)ylene includes lower alk(en)(yn)ylene. There may beoptionally inserted along the alkynylene group one or more oxygen,sulfur or substituted or unsubstituted nitrogen atoms, where thenitrogen substituent is alkyl. Alk(en)(yn)ylene groups include, but arenot limited to, —C═C—(CH₂)_(n)—C≡C—, where n is 1 or 2. The term “loweralk(en)(yn)ylene” refers to alk(en)(yn)ylene groups having up to 6carbons. In certain embodiments, alk(en)(yn)ylene groups have about 4carbon atoms.

As used herein, “cycloalkylene” refers to a divalent saturated mono- ormulticyclic ring system, in certain embodiments of 3 to 10 carbon atoms,in other embodiments 3 to 6 carbon atoms; cycloalkenylene andcycloalkynylene refer to divalent mono- or multicyclic ring systems thatrespectively include at least one double bond and at least one triplebond. Cycloalkenylene and cycloalkynylene groups may, in certainembodiments, contain 3 to 10 carbon atoms, with cycloalkenylene groupsin certain embodiments containing 4 to 7 carbon atoms andcycloalkynylene groups in certain embodiments containing 8 to 10 carbonatoms. The ring systems of the cycloalkylene, cycloalkenylene andcycloalkynylene groups may be composed of one ring or two or more ringswhich may be joined together in a fused, bridged or spiro-connectedfashion. “Cycloalk(en)(yn)ylene” refers to a cycloalkylene groupcontaining at least one double bond and at least one triple bond.

As used herein, “substituted alkylene,” “substituted alkenylene,”“substituted alkynylene,” “substituted cycloalkylene,” “substitutedcycloalkenylene,” and “substituted cycloalkynylene” refer to alkylene,alkenylene, alkynylene, cycloalkylene, cycloalkenylene andcycloalkynylene groups, respectively, that are substituted with one ormore substituents, in certain embodiments one to three or foursubstituents, where the substituents are as defined herein, generallyselected from Q¹.

As used herein, “arylene” refers to a monocyclic or polycyclic, incertain embodiments monocyclic, divalent aromatic group, in oneembodiment having from 5 to about 20 carbon atoms and at least onearomatic ring, in another embodiment 5 to 12 carbons. In furtherembodiments, arylene includes lower arylene. Arylene groups include, butare not limited to, 1,2-, 1,3- and 1,4-phenylene. The term “lowerarylene” refers to arylene groups having 5 or 6 carbons.

As used herein, “heteroarylene” refers to a divalent monocyclic ormulticyclic aromatic ring system, in one embodiment of about 5 to about15 members where one or more, in certain embodiments 1 to 3, of theatoms in the ring system is a heteroatom, that is, an element other thancarbon, including but not limited to, nitrogen, oxygen or sulfur.

As used herein, “heterocyclylene” refers to a divalent monocyclic ormulticyclic non-aromatic ring system, in certain embodiments of 3 to 10members, in one embodiment 4 to 7 members, in another embodiment 5 to 6members, where one or more, including 1 to 3, of the atoms in the ringsystem is a heteroatom, that is, an element other than carbon, includingbut not limited to, nitrogen, oxygen or sulfur.

As used herein, “substituted arylene,” “substituted heteroarylene” and“substituted heterocyclylene” refer to arylene, heteroarylene andheterocyclylene groups, respectively, that are substituted with one ormore substituents, in certain embodiments one to three of foursubstituents, where the substituents are as defined herein, generallyselected from Q¹.

As used herein, “alkylidene” refers to a divalent group, such as ═CR′R″,which is attached to one atom of another group, forming a double bond.Alkylidene groups include, but are not limited to, methylidene (═CH₂)and ethylidene (═CHCH₃). As used herein, “arylalkylidene” refers to analkylidene group in which either R′ or R″ is an aryl group.“Cycloalkylidene” groups are those where R′ and R″ are linked to form acarbocyclic ring. “Heterocyclylidene” groups are those where at leastone of R′ and R″ contain a heteroatom in the chain, and R′ and R″ arelinked to form a heterocyclic ring.

As used herein, “amido” refers to the divalent group —C(O)NH—.“Thioamido” refers to the divalent group —C(S)NH—. “Oxyamido” refers tothe divalent group —OC(O)NH—. “Thiaamido” refers to the divalent group—SC(O)NH—. “Dithiaamido” refers to the divalent group —SC(S)NH—.“Ureido” refers to the divalent group —HNC(O)NH—. “Thioureido” refers tothe divalent group —HNC(S)NH—.

As used herein, “semicarbazide” refers to —NHC(O)NHNH—. “Carbazate”refers to the divalent group —OC(O)NHNH—. “Isothiocarbazate” refers tothe divalent group —SC(O)NHNH—. “Thiocarbazate” refers to the divalentgroup —OC(S)NHNH—. “Sulfonylhydrazide” refers to the group —SO₂NHNH—.“Hydrazide” refers to the divalent group —C(O)NHNH—. “Azo” refers to thedivalent group —N═N—. “Hydrazinyl” refers to the divalent group —NH—NH—.

Where the number of any given substituent is not specified (e.g.,“haloalkyl”), there may be one or more substituents present. Forexample, “haloalkyl” may include one or more of the same or differenthalogens. As another example, “C₁₋₃alkoxyphenyl” may include one or moreof the same or different alkoxy groups containing one, two or threecarbons.

As used herein, the following terms have their accepted meaning in thechemical literature:

AcOH acetic acid CHCl₃ chloroform conc concentrated DBU1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DME1,2-dimethoxyethane DMF N,N-dimethylformamide DMSO dimethylsulfoxideEtOAc ethyl acetate EtOH ethanol (100%) Et₂O diethyl ether Hex hexanesH₂SO₄ sulfuric acid MeCN acetonitrile MeOH methanol Pd/C palladium onactivated carbon TEA triethylamine THF tetrahydrofuran TFAtrifluoroacetic acid

As used herein, the abbreviations for any protective groups, amino acidsand other compounds, are, unless indicated otherwise, in accord withtheir common usage, recognized abbreviations, or the IUPAC-IUBCommission on Biochemical Nomenclature (see, (1972) Biochem.11:942-944).

B. Heterocyclic Modulators of Nuclear Receptors

Compounds for use in compositions and methods for modulating theactivity of nuclear receptors are provided. In particular, compounds foruse in compositions and methods for modulating farnesoid X receptor(FXR), liver X receptors (LXRα and LXRβ) and/or orphan nuclearreceptors, are provided.

In certain embodiments, the compounds are thiazolidinones, i.e.,compounds of formulae I where X² is S and X³ is O, that are substitutedwith a heterocyclylene group and an imine moiety. Thus, in theseembodiments, the compounds have formulae II:

or a pharmaceutically acceptable derivative thereof, where A, D, E and Gare selected from (i) or (ii) as follows:

(i) A and G are each independently selected from hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedheterocyclyalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaralkyl, substituted or unsubstitutedheteroarylium, substituted or unsubstituted heteroaryliumalkyl, halo,pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, NR¹¹R¹² and C(═J)R¹³, or A and Gtogether form substituted or unsubstituted alkylene, substituted orunsubstituted azaalkylene, substituted or unsubstituted oxaalkylene,substituted or unsubstituted thiaalkylene, substituted or unsubstitutedalkenylene, substituted or unsubstituted alkynylene, substituted orunsubstituted 1,3-butadienylene, substituted or unsubstituted1-aza-1,3-butadienylene, or substituted or unsubstituted2-aza-1,3-butadienylene.

 D and E are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocylyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo and pseudohalo or D and E togetherform a bond; or

(ii) A and D; or E and G; together form substituted or unsubstitutedalkylene, substituted or unsubstituted azaalkylene, substituted orunsubstituted oxaalkylene, or substituted or unsubstituted thiaalkylene;and the others of A, D, E and G are selected as in (i);

X¹ is selected from O, S, S(═O), S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; R¹and R² are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; where:

R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo,OR¹⁰, NR¹⁴R¹⁵ and C(═J)R¹³;

R¹⁰, R¹¹ and R¹² are each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl or C(═J)R¹³;

J is O, S or NR¹⁴;

R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵;

R¹⁴, R¹⁵ and R¹⁶ are each independently selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl;

where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylium,aralkyl, heteroaralkyl and heteroaryliumalkyl moieties of R¹, R², R³,R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted orsubstituted with one or more substituents each independently selectedfrom Q¹, where Q¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile,nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl,haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy,aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo,arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—)or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is 1or 2; or two Q¹ groups, which substitute the same atom, together formalkylene;

each Q¹ is independently unsubstituted or substituted with one or moresubstituents each independently selected from Q²;

each Q² is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile,nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl,haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy,aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—)or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is 1or 2; or two Q² groups, which substitute the same atom, together formalkylene;

each Q2 group is independently unsubstituted or substituted with one ormore, in one embodiment one, two or three, substituents eachindependently selected from alkyl, halo and pseudohalo;

R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, arylor —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene;

R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl;

R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl or heterocyclylalkyl;

R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹.

In another embodiment, the compounds have formulae II:

or a pharmaceutically acceptable derivative thereof, where A, D, E and Gare selected from (i) or (ii) as follows:

(i) A and G are each independently selected from hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted cycloalkylalkyl, substituted or unsubstitutedheterocyclylalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted aralkyl,substituted or unsubstituted heteroaralkyl, substituted or unsubstitutedheteroarylium, substituted or unsubstituted heteroaryliumalkyl, halo,pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³, or Aand G together form substituted or unsubstituted alkylene, substitutedor unsubstituted azaalkylene, substituted or unsubstituted oxaalkylene,substituted or unsubstituted thiaalkylene, substituted or unsubstitutedalkenylene, substituted or unsubstituted alkynylene, substituted orunsubstituted 1,3-butadienylene, substituted or unsubstituted1-aza-1,3-butadienylene, or substituted or unsubstituted2-aza-1,3-butadienylene;

 D and E are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo and pseudohalo or D and E togetherform a bond; or

(ii) A and D; or E and G; together form substituted or unsubstitutedalkylene, substituted or unsubstituted azaalkylene, substituted orunsubstituted oxaalkylene, or substituted or unsubstituted thiaalkylene;and the others of A, D, E and G are selected as in (i);

X¹ is selected from O, S, S(═O), S(═O)₂, Se, NR⁵, CR⁵R⁷ and CR⁸═CR⁹; R¹and R² are each independently selected from hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; R³ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted heteroarylium, substituted orunsubstituted aralkyl, substituted or unsubstituted heteroaralkyl,substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; where:

R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo,OR¹⁰, NR¹⁴R¹⁵ and C(═J)R¹³;

R¹⁰, R¹¹ and R¹² are each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl or C(═J)R¹³;

J is O, S or NR¹⁴;

R¹³ is selected from hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵;

R¹⁴, R¹⁵ and R¹⁶ are each independently selected from hydrogen, alkyl,alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl;

where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylium,aralkyl, heteroaralkyl and heteroaryliumalkyl moieties of R¹, R², R³,R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted orsubstituted with one or more substituents each independently selectedfrom Q¹, where Q¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile,nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl,haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy,aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—)or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is 1or 2; or two Q¹ groups, which substitute the same atom, together formalkylene;

each Q¹ is independently unsubstituted or substituted with one or moresubstituents each independently selected from Q²;

each Q² is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile,nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl,haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy,aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)2,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH2)_(y)—O—)or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is 1or 2; or two Q² groups, which substitute the same atom, together formalkylene;

R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, arylor —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene;

R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl;

R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl or heterocyclylalkyl;

R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹.

In another embodiment, A and G are each independently selected fromhydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted aryl, or together form substituted or unsubstituted1,3-butadienyl. In a further embodiment, A and G are each independentlyhydrogen, substituted or unsubstituted methyl, substituted orunsubstituted naphthyl, or substituted or unsubstituted phenyl, ortogether form 1,3-butadienyl. In another embodiment, A and G are bothhydrogen.

In another embodiment, D and E are each hydrogen, or together form abond.

In another embodiment, the compounds for use in the compositions andmethods provided herein have formulae I where D and E together form abond, and A and G together form 1,3-butadienyl. Thus, in thisembodiment, the compounds have formulae III:

or a pharmaceutically acceptable derivative thereof, where R¹, R², R³,X¹, X² and X³ are selected as above; each R⁴ is independentlysubstituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl, substituted orunsubstituted guanidino, substituted or unsubstituted isothioureido,halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² or C(═J)R¹³;x is an integer from 0 to 4; and the amino, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl,heteroaryl, heteroarylium, aralkyl, heteroaralkyl and heteroaryliumalkylmoieties of R⁴ are unsubstituted or substituted with one or moresubstituents each independently selected from Q², as defined above.

In another embodiment, the compounds for use in the compositions andmethods provided herein have formulae IV:

or a pharmaceutically acceptable derivative thereof, where R¹, R², R³,X¹, X² and X³ are selected as above; each R⁴ is independentlysubstituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl, substituted orunsubstituted guanidino, substituted or unsubstituted isothioureido,halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² or C(═J)R¹³;x is an integer from 0 to 4; and the amino, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl,heteroaryl, heteroarylium, aralkyl, heteroaralkyl and heteroaryliumalkylmoieties of R⁴ are unsubstituted or-substituted with one or more, incertain embodiments one to three or four, substituents eachindependently selected from Q², as defined above.

In certain embodiments herein, the compounds are of formulae III or IV,and are selected with the proviso that when R³ is substituted orunsubstituted heteroarylium then the heteroatom substituent is not alkylor aryl. In another embodiment, the compounds are of formulae III or IV,and are selected with the proviso that R³ is not substituted orunsubstituted heteroarylium or substituted or unsubstitutedheteroaryliumalkyl. In other embodiments, the compounds are of formulaIII or IV and are selected with the proviso that R³ is not heteroaryl.In further embodiments, the compounds are of formula III or IV and areselected with the proviso that R³ is not alkyl. In another embodiment,the compounds are of formula III or IV and are selected with the provisothat R³ is not heterocycloaryl (i.e., an aryl groups possessing a fusedheterocyclic moiety).

In certain embodiments herein, X¹ is O, S or NR⁵. In other embodiments,X¹ is O or S. In another embodiment, X¹ is S.

In other embodiments, R¹ is substituted or unsubstituted alkyl. Infurther embodiments, R¹ is methyl.

In another embodiment, R² is substituted or unsubstituted alkyl orsubstituted or unsubstituted aralkyl. In further embodiments, R² isethyl, n-butyl or benzyl. In another embodiment, R² is benzyl. Inanother embodiment, R² is substituted or unsubstituted heteroaralkyl. Inanother embodiment, R² is pyridylmethyl. In another embodiment, R² ispicolyl (i.e., 2-, 3-, or 4-pyridylmethyl). In another embodiment, R² is2-furylmethyl. In another embodiment, R² is 3-pyridylmethyl.

In another embodiment, R³ is substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl. In further embodiments, R³ issubstituted or unsubstituted phenyl, substituted or unsubstitutednaphthyl, substituted or unsubstituted pyridyl, substituted orunsubstituted indazolyl, or substituted or unsubstituted quinolinyl. Inanother embodiment, R³ is substituted or unsubstituted quinolyl,substituted or unsubstituted phenyl, substituted or unsubstitutednaphthyl, substituted or unsubstituted isoquinolyl, substituted orunsubstituted pyridyl, or substituted or unsubstituted indazolyl. Incertain embodiments, R³ is substituted or unsubstituted phenyl orsubstituted or unsubstituted naphthyl. In another embodiment, R³ issubstituted or unsubstituted phenyl.

In another embodiment, Q¹ is selected from halo, hydroxy, nitrile,nitro, hydroxycarbonyl, alkyl, haloalkyl, polyhaloalkyl, heteroaryl,alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkoxy, perfluoroalkoxy,aralkoxy, hydroxyimino, alkoxyimino, aralkoxyimino, arylazo,haloalkylcarbonylamino, amino, alkylamino, dialkylamino, haloalkylamino,alkylcarbonylamino, dialkylcarbonyloxy or heterocyclyl; or two Q¹groups, which substitute atoms in a 1,2 arrangement, form alkylenedioxy.In another embodiment, Q¹ is selected from halo, hydroxy, nitrile,nitro, hydroxycarbonyl, alkyl, haloalkyl, polyhaloalkyl, heteroaryl,alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkoxy, perfluoroalkoxy,aralkoxy, amino, alkylamino, dialkylamino, haloalkylamino,alkylcarbonylamino, dialkylcarbonyloxy or heterocyclyl; or two Q¹groups, which substitute atoms in a 1,2 arrangement, form alkylenedioxy.In further embodiments, Q¹ is methoxy, dimethylamino, NH₂, benzyloxy,hydroxy, CN, isopropyl, methyl, nitro, ethylamino, trifluoromethyl,acetyl, chloro, n-propyl, ethoxy, methylcarbonylamino, CONH₂,methoxycarbonyl, methylamino, trifluoromethoxy, imidazolyl,hydroxycarbonyl, isopropylamino, tert-butylamino,2,2,2-trifluoroethylamino, piperidinyl, dimethylaminocarbonyloxy,2-hydroxyethoxy, 2-(N-morpholinyl)ethoxy or morpholinyl, or two Q¹groups, which substitute atoms in a 1,2 arrangement, formmethylenedioxy. In another embodiment, Q¹ is hydroxycarbonyl orethylamino.

In further embodiments, the compounds for use in the compositions andmethods provided herein are of formulae IV where x is 0, R¹ is methyl,R² is benzyl, X¹ is S and R³ is a substituted or unsubstituted phenylgroup. Thus, in these embodiments, the compounds have formulae V:

or a pharmaceutically acceptable derivative thereof, where R¹⁷, R¹⁸,R¹⁹, R²⁰ and R²¹ are each independently selected from hydrogen, halo,pseudohalo, hydroxyl, nitrile, nitro, formyl, mercapto, hydroxycarbonyl,hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl,diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl,heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl,triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl,aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl,diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, guanidino, isothioureido,ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl, or any two of R¹⁷, R¹⁸,R¹⁹, R²⁰ and R²¹, which substitute adjacent carbons on the ring,together form alkylenedioxy; and

the aryl and heteroaryl groups of R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ areunsubstituted or substituted with one or more substituents, in oneembodiment one to three or four substituents, each independentlyselected from R³⁰, where R³⁰ is alkyl, halo, pseudohalo, alkoxy, aryloxyor alkylenedioxy.

In another embodiment, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independentlyselected from hydrogen, halo, hydroxy, nitrile, nitro, hydroxycarbonyl,alkyl, haloalkyl, polyhaloalkyl, heteroaryl, alkylcarbonyl,alkoxycarbonyl, aminocarbonyl, alkoxy, perfluoroalkoxy, aralkoxy, amino,alkylamino, dialkylamino, haloalkylamino, alkylcarbonylamino orheterocyclyl; or any two of R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹, which substituteadjacent carbons on the ring, form alkylenedioxy. In furtherembodiments, R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently hydrogen,methoxy, dimethylamino, NH₂, benzyloxy, hydroxy, CN, isopropyl, methyl,nitro, ethylamino, trifluoromethyl, acetyl, chloro, n-propyl, ethoxy,methylcarbonylamino, CONH₂, methoxycarbonyl, methylamino,trifluoromethoxy, imidazolyl, hydroxycarbonyl, isopropylamino,tert-butylamino, 2,2,2-trifluoroethylamino, piperidinyl or morpholinyl,or any two of R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹, which substitute adjacentcarbons on the ring, form methylenedioxy.

In another embodiment, A is phenyl which is unsubstituted or issubstituted with one or more, in one embodiment, one, two or three,groups each independently selected from Q¹.

In another embodiment, the compounds for use in the compositions andmethods provided herein have formulae II where X¹ is S; R¹ is methyl; R²is benzyl; A is phenyl; G is hydrogen; and D and E together form a bond.Thus, in this embodiment, the compounds have formulae VI:

or a pharmaceutically acceptable derivative thereof, where R¹⁷, R¹⁸,R¹⁹, R²⁰ and R²¹ are selected as above.

In another embodiment, the compounds for use in the compositions andmethods provided herein have formulae II where X¹ is S; R¹ is methyl; R²is benzyl; A and G are hydrogen; and D and E together form a bond. Thus,in this embodiment, the compounds have formulae VII:

or a pharmaceutically acceptable derivative thereof, where R¹⁷, R¹⁸,R¹⁹, R²⁰ and R²¹ are selected as above.

In another embodiment, the compounds for use in the compositions andmethods provided herein have formulae II where X¹ is S; R¹ is methyl; R²is benzyl; and A, G, D and E are hydrogen. Thus, in this embodiment, thecompounds have formulae VIII:

or a pharmaceutically acceptable derivative thereof, where R¹⁷, R¹⁸,R¹⁹, R²⁰ and R²¹ are selected as above.

In another embodiment, the compounds for use in the compositions andmethods provided herein have formulae II where X¹ is S; R¹ is methyl; R²is benzyl; A is phenyl; G is methyl; and D and E together form a bond.Thus, in this embodiment, the compounds have formulae IX:

or a pharmaceutically acceptable derivative thereof, where R¹⁷, R¹⁸,R¹⁹, R²⁰ and R²¹ are selected as above.

In another embodiment, the compounds provided herein have formulae V-XI,where R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently selected from(i) or (ii) as follows:

(i) R²¹ is ethylamino; R¹⁸ is cyano; and R¹⁷, R¹⁹ and R²⁰ are eachhydrogen; or

(ii) R¹⁷ is ethylamino; R²⁰ is cyano; and R¹⁸, R¹⁹ and R²¹ are eachhydrogen.

In certain embodiments, the compounds have formulae I, where X¹, X² andX³ are selected from (i) or (ii) as follows: (i) X¹, X² and X³ are eachindependently S, O or NR⁵; or (ii) X¹ is —CR⁸═CR⁹—, where R⁸ and R⁹ areas defined herein, and X² and X³ are each independently S, O or NR⁵; R¹is substituted or unsubstituted alkyl, where there are 0 to 6substituents selected from alkoxy, alkoxyalkyl, hydroxycarbonyl,alkylcarbonyloxy, hydroxy, halo, pseudohalo, aryl and heteroaryl; R² issubstituted or unsubstituted aralkyl, substituted or unsubstituted aryl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heteroaralkyl, or substituted or unsubstitutedheterocyclylalkyl; where there are 0 or 1 substituents selected fromalkoxycarbonyl and hydroxycarbonyl; R³ is substituted or unsubstitutedheteroaryl, substituted or unsubstituted aryl, or substituted orunsubstituted aralkyl; where there are 0 to 5 substituents selected fromalkylamino, cyano, cycloalkyl, hydroxy, alkoxy, dialkylamino, amino,heterocyclyl, aralkoxy, alkyl, nitro, haloalkyl, alkylcarbonyl, halo,alkylcarbonylamino, alkoxyalkylcarbonylamino,dialkylaminoalkylcarbonylamino, aminocarbonyl, alkoxycarbonyl,aralkylamino, cycloalkylamino, heterocyclylamino, haloalkylamino,haloalkoxy, hydroxycarbonyl, aminosulfonyl, alkylcarbonylaminosulfonyl,or haloalkylcarbonylamino, or any two substituents, which substituteatoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy; A and Gare each independently selected from hydrogen, substituted orunsubstituted aryl, substituted or unsubstituted alkyl, substituted orunsubstituted alkoxycarbonyl, hydroxycarbonyl, and substituted orunsubstituted alkylcarbonyl, where there are 0 to 5 substituentsselected from aryl, haloalkyl, haloalkoxy, nitro, halo, pseudohalo,hydroxy, alkyl and alkoxy, or A and G together form substituted orunsubstituted alkylene, substituted or unsubstituted azaalkylene orsubstituted or unsubstituted 1,3-butadienylene, in one embodimentsubstituted or unsubstituted alkylene, where there are 0 to 4substituents selected from halo, pseudohalo, alkoxy, nitro, haloalkyl,alkylcarbonylamino, hydroxy, alkylaminocarbonyloxy,alkoxycarbonylalkoxy, aminocarbonylalkoxy, hydroxyalkoxy, alkyl,haloalkylaminocarbonyloxy and alkylaminoalkoxy; D and E are eachhydrogen, or together form a bond; and R⁵ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³,S(═O)₂R¹³, NR¹⁴R¹⁵ or C(═J)R¹³; R¹⁰ is hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl or C(═J)R¹³; J is O, S or NR¹⁴; R¹³ isselected from hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted cycloalkylalkyl, substitutedor unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl, pseudohalo, OR¹⁶and NR¹⁴R¹⁵; R¹⁴, R¹⁵ and R¹⁶ are each independently selected fromhydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl andheteroaralkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl and heteroaralkyl moieties of R⁵, R¹⁰ and R¹³ are unsubstitutedor substituted with one or more substituents each independently selectedfrom Q¹, where Q¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile,nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl,haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl,cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl,aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl,dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene,arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl,alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl,aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl,arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl,arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy,heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy,aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy,alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy,aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino,hydroxyimino, alkoxyimino, aralkoxyimino, arylazo,haloalkylcarbonylamino, aminothiocarbonyl, alkylaminothiocarbonyl,arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl,dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl,alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino,arylamino, diarylamino, alkylarylamino, alkylcarbonylamino,alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino,arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—)or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is 1or 2; or two Q² groups, which substitute the same atom, together formalkylene;

R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, arylor —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene;

R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl;

R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl or heterocyclylalkyl;

R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹.

In certain embodiments, the compounds have formulae I, where X¹, X² andX³ are each independently S, O or NR⁵; R¹ is substituted orunsubstituted alkyl, where there are 0 to 6 substituents selected fromhalo, pseudohalo, aryl and heteroaryl; R² is substituted orunsubstituted aralkyl, substituted or unsubstituted aryl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted heteroaralkyl,or substituted or unsubstituted heterocyclylalkyl; where there are 0 or1 substituents selected from alkoxycarbonyl and hydroxycarbonyl; R³ issubstituted or unsubstituted heteroaryl, substituted or unsubstitutedaryl, or substituted or unsubstituted aralkyl; where there are 0 to 5substituents selected from alkylamino, cyano, cycloalkyl, hydroxy,alkoxy, dialkylamino, amino, heterocyclyl, aralkoxy, alkyl, nitro,haloalkyl, alkylcarbonyl, halo, alkylcarbonylamino, aminocarbonyl,alkoxycarbonyl, aralkylamino, cycloalkylamino, heterocyclylamino,haloalkylamino, haloalkoxy, hydroxycarbonyl, aminosulfonyl,alkylcarbonylaminosulfonyl, or haloalkylcarbonylamino, or any twosubstituents, which substitute atoms in a 1,2 or 1,3 arrangement,together form alkylenedioxy; A and G are each independently selectedfrom hydrogen, substituted or unsubstituted aryl, substituted orunsubstituted alkyl and substituted or unsubstituted alkylcarbonyl,where there are 0 to 5 substituents selected from nitro, halo,pseudohalo, alkyl and alkoxy, or A and G together form substituted orunsubstituted alkylene or substituted or unsubstituted1,3-butadienylene, in one embodiment substituted or unsubstitutedalkylene, where there are 0 to 4 substituents selected from halo,pseudohalo, alkoxy, nitro, haloalkyl, alkylcarbonylamino, hydroxy,alkylaminocarbonyloxy, alkoxycarbonylalkoxy, aminocarbonylalkoxy,hydroxyalkoxy, alkyl, haloalkylaminocarbonyloxy and alkylaminoalkoxy; Dand E are each hydrogen, or together form a bond; and R⁵ is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo,OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹⁴R¹⁵ or C(═J)R¹³; R¹⁰ is hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted cycloalkylalkyl, substituted orunsubstituted heterocyclylalkyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, substituted or unsubstituted heteroaralkyl or C(═J)R¹³; J is O,S or NR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedcycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted aralkyl, substituted orunsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ andR¹⁶ are each independently selected from hydrogen, alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl,aryl, heteroaryl, aralkyl and heteroaralkyl moieties of R⁵, R¹⁰ and R¹³are unsubstituted or substituted with one or more substituents eachindependently selected from Q¹, where Q¹ is halo, pseudohalo, hydroxy,oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl,hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl,diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl,heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl,heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl,triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl,heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl,aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl,aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl,diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy,heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy,, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups,which substitute the same atom, together form alkylene; each Q¹ isindependently unsubstituted or substituted with one or more substituentseach independently selected from Q²; each Q² is independently halo,pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto,hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl,aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds,alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl,heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl,aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl,alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene,alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl,alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl,aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy,aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy,perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy,arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy,aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy,alkylaminocarbonyloxy, dialkylaminocarbonyloxy,alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino,isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido,N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido,N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido,N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido,N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido,N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido,N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino,aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino,aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl,diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino,haloalkylamino, arylamino, diarylamino, alkylarylamino,alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino,arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl,aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino,arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino,heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵)₂, OP(═O)(R⁵⁰)₂,—NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl,hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio,hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy,alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy,alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy,dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy,alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl,arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl,diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, whichsubstitute atoms in a 1,2 or 1,3 arrangement, together formalkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e.,—S—(CH₂)_(y)—O—)or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is 1or 2; or two Q² groups, which substitute the same atom, together formalkylene;

R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, arylor —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl,aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹together form alkylene, azaalkylene, oxaalkylene or thiaalkylene;

R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl;

R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl or heterocyclylalkyl;

R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or—NR⁷⁰R⁷¹.

In certain embodiments, the compounds claimed herein exhibit improved invitro activity, efficacy, potency and/or pharmacokinetic properties,such as solubility, oral half-life, bioavailability, oral absorption,and/or in vivo activity, over related commercially available compoundsor related compounds disclosed previously.

In certain embodiments, A and G are selected with the proviso that A andG are not both methyl. In another embodiment, A and G together formbutadienyl with the proviso that the resulting benzo-fused group is notsubstituted at the 5-position with methoxy or chloro and is notsubstituted at the 6-position with methoxy or methyl. In anotherembodiment, A and G together form butadienyl with the proviso that theresulting benzo-fused group is not substituted at the 5-position withalkoxy or halo and is not substituted at the 6-position with alkoxy oralkyl. In another embodiment, A and G together form butadienyl with theproviso that the resulting benzo-fused group is not substituted withmethoxy, methyl or chloro. In another embodiment, A and G together formbutadienyl with the proviso that the resulting benzo-fused group is notsubstituted with alkoxy, alkyl or halo.

In another embodiment, X¹ is S. In another embodiment, X¹ is —CR⁸═CR⁹—.In another embodiment, X² is S. In another embodiment, X³ is O.

In another embodiment, R¹ is substituted alkyl. In another embodiment,R¹ is 2-methoxy-1-ethyl, 3-methoxy-1-propyl, methoxycarbonylmethyl,hydroxycarbonylmethyl, 2-acetoxy-1-ethyl or 2-hydroxy-1-ethyl. Inanother embodiment, R¹ is unsubstituted alkyl. In other embodiments, R¹is methyl.

In another embodiment, R² is benzyl, phenyl, allyl, ethyl, butyl,cyclohexyl, propyl, 3-pyridylmethyl, 2-furylmethyl,4-methoxycarbonylbenzyl, 4-hydroxycarbonylbenzyl, 2-phenethyl or2-(4-morpholinyl)ethyl. In another embodiment, R² is benzyl. In anotherembodiment, R² is pyridylmethyl. In another embodiment, R² is picolyl(i.e., 2-, 3-, or 4-pyridylmethyl). In another embodiment, R² is2-furylmethyl. In another embodiment, R² is 3-pyridylmethyl.

In another embodiment, R³ is substituted or unsubstituted quinolyl,substituted or unsubstituted phenyl, substituted or unsubstitutednaphthyl, substituted or unsubstituted isoquinolyl, substituted orunsubstituted pyridyl, or substituted or unsubstituted indazolyl. Inanother embodiment, R³ is substituted or unsubstituted phenyl. In otherembodiments, R³ is substituted with 0 to 5 substituents selected fromethylamino, cyano, cyclohexyl, hydroxy, methoxy, dimethylamino, amino,4-morpholinyl, methylamino, isopropylamino, benzyloxy, methyl,isopropyl, nitro, trifluoromethyl, methylcarbonyl, chloro, propyl,ethoxy, methylcarbonylamino, aminocarbonyl, methoxycarbonyl,methoxymethylcarbonylamino, dimethylaminomethylcarbonylamino,butylamino, benzylamino, cyclopentylamino, 1-pyrrolidinylamino,pyrrolidinyl, t-butylamino, 2,2,2-trifluoroethylamino, piperidinyl,trifluoromethoxy, hydroxycarbonyl, aminosulfonyl,methylcarbonylaminosulfonyl, trifluoromethylcarbonylamino andt-butoxycarbonyl, or any two substituents, which substitute atoms in a1,2 arrangement, together form methylenedioxy. In further embodiments,R³ is 5-quinolyl, 2-ethylamino-5-cyanophenyl, 4-cyclohexylphenyl,2-hydroxy-1-naphthyl, 6-quinolyl, 3-methoxyphenyl,4-dimethylaminophenyl, 4-aminophenyl, 4-(4-morpholinyl)phenyl,2-methylamino-5-cyanophenyl, 2-dimethylamino-5-cyanophenyl,2-ethylaminophenyl, 3-cyanophenyl, 2-aminophenyl,2-isopropylamino-5-cyanophenyl, 4-benzyloxyphenyl,2-methyl4-hydroxy-5-isopropylphenyl, 2-ethylamino-5-nitrophenyl,3-trifluoromethylphenyl, 3-methylcarbonylphenyl, 3-chlorophenyl,2-propylphenyl, 2-ethoxyphenyl, 3-methylcarbonylaminophenyl,3-aminocarbonylphenyl, 3-methoxycarbonylphenyl, 8-quinolyl,8-hydroxy-5-quinolyl, 2-butylamino-5-cyanophenyl,2-benzylamino-5-cyanophenyl, 2-cyclopentylamino-5-cyanophenyl,2-(1-pyrrolidinyl)amino-5-cyanophenyl, 5-isoquinolyl, 1-isoquinolyl,4-methylcarbonylaminophenyl, 2-t-butylamino-5-cyanophenyl,2-(2,2,2-trifluoroethyl)amino-5-cyanophenyl,2-piperidinyl-5-cyanophenyl, 4-methylcarbonylphenyl,4-aminocarbonylphenyl, 2-ethylamino-5-methoxymethylcarbonylaminophenyl,2-ethylamino-5-dimethylaminomethyl-carbonylaminophenyl, 1-naphthyl,2-naphthyl, 2-pyridyl, 3-pyridyl, 2-ethoxy-5-methylcarbonylaminophenyl,4-pyridyl, 4-methoxycarbonylphenyl, 4-trifluoromethoxyphenyl,5-indazolyl, 4-(imidazol-1-yl)phenyl, 3,4-methylenedioxyphenyl,3-hydroxycarbonylphenyl, 2-ethylamino-5-methylcarbonylphenyl,4-aminosulfonylphenyl, 4-methylcarbonylaminosulfonylphenyl,3-methylcarbonylphenyl, 2-methylcarbonylamino-5-pyridyl,4-cyano-3-methylcarbonylaminophenyl,2-methylamino-5-methylcarbonylphenyl,4-trifluoromethylcarbonylaminophenyl,2-ethylamino-5-methoxycarbonylphenyl, 2-hydroxycarbonylphenyl or2-ethylamino-5-t-butoxycarbonylphenyl.

In another embodiment, A and G are each independently selected fromhydrogen, substituted or unsubstituted phenyl, substituted orunsubstituted methyl, substituted or unsubstituted naphthyl,hydroxycarbonyl, substituted and unsubstituted ethoxycarbonyl, andsubstituted or unsubstituted methylcarbonyl, or A and G together fromsubstituted or unsubstituted butylene, substituted or unsubstitutedpropylene, substituted or unsubstituted methyleneazaethylene, orsubstituted or unsubstituted 1,3-butadienylene. In other embodiments, Aand G are each independently selected from hydrogen, substituted orunsubstituted phenyl, substituted or unsubstituted methyl, substitutedor unsubstituted naphthyl, and substituted or unsubstitutedmethylcarbonyl, and are substituted with 0 to 4 substituents selectedfrom chloro, bromo, methoxy, fluoro, ethoxy, nitro,trifluoromethylcarbonylamino, dimethylaminocarbonyloxy,2-(1-piperidinyl)ethoxy, 2-(1-methyl-4-piperazinyl)ethoxy,2-(N-morpholinyl)ethoxy, 2-dimethylaminoethoxy, hydroxycarbonylmethoxy,methylcarbonylamino, phenyl, trifluoromethyl, trifluoromethoxy, hydroxy,ethylaminocarbonyloxy, methoxycarbonyl methoxy, aminocarbonylmethoxy,2-hydroxyethoxy, 2-hydroxypropoxy, methyl, 2-chloroethylaminocarbonyloxyand 2-methylaminoethoxy. In further embodiments, A and G together formsubstituted or unsubstituted 1,3-butadienylene and are substituted with0 to 5 substituents selected from nitro, fluoro, chloro, methyl andmethoxy. In another embodiment, A and G are each independently selectedfrom hydrogen, 4-phenylphenyl, 4-trifluoromethylphenyl,2-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-nitrophenyl,4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-methoxyphenyl, methyl,2-naphthyl, 4-bromophenyl, 2-methoxyphenyl, 3-fluorophenyl,2,4-dimethoxyphenyl, ethoxycarbonyl, benzyl, hydroxycarbonyl,2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, phenyl andmethylcarbonyl, or A and G together form 1,3-butadienylene,2-chloro-1,3-butadienylene, 2-methoxy-1,3-butadienylene,2-fluoro-1,3-butadienylene, 2-ethoxy-1,3-butadienylene,2-nitro-1,3-butadienylene, 2-trifluoromethyl-1,3-butadienylene,2-trifluoromethoxy-1,3-butadienylene,2-methylcarbonylamino-1,3-butadienylene, 2-trifluoromethylcarbonylamino-1,3-butadienylene, 2-aminocarbonylmethoxy-1,3-butadienylene,2-(2-hydroxyethoxy)-1,3-butadienylene,2-(3-hydroxypropoxy)-1,3-butadienylene,2-dimethylaminocarbonyloxy-1,3-butadienylene,2-(1-piperidinyl)ethoxy-1,3-butadienylene,2-(4-(1-methylpiperazin)yl)ethoxy-1,3-butadienylene,2-(4-morpholinyl)ethoxy-1,3-butadienylene,2-dimethylaminoethoxy-1,3-butadienylene,2-hydroxycarbonylmethoxy-1,3-butadienylene, 2-hydroxy-1,3-butadienylene,2-ethylaminocarbonyloxy-1,3-butadienylene,2-methoxycarbonylmethoxy-1,3-butadienylene,2-aminocarbonylmethoxy-1,3-butadienylene,2-(2-hydroxyethoxy)-1,3-butadienylene, 1-methoxy-1,3-butadienylene,1-methyl-1,3-butadienylene, 1-chloro-1,3-butadienylene,2-(2-chloroethylaminocarbonyloxy)-1,3-butadienylene or2-(2-methylaminoethoxy)-1,3-butadienylene.

In another embodiment, D and E are each hydrogen or together form abond.

In certain embodiments herein, the compounds are selected from thefollowing compounds. In other embodiments, the compounds are selectedfrom those disclosed in the Examples. All isomers of these compounds arewithin the scope of the disclosure herein:

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-phenylimino-thiazolidine-4-one;

3-benzyl-2-(4-methoxyphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;

3-benzyl-2-(4-dimethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;

2-(4-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-6-ylimino)-thiazolidine-4-one;

2-(2-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;

3-benzyl-2-(4-benzyloxyphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;

3-benzyl-2-(2-hydroxy-1-naphthylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;

3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile;

3-benzyl-2-(4-hydroxy-5-isopropyl-2-methylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;

3-benzyl-2-(2-ethylamino-5-nitrophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-[3-(trifluoromethyl)-phenylimino]thiazolidine-4-one;

2-(3-acetylphenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;

3-benzyl-2-(3-chlorophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-propyl-phenylimino)thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-5-ylimino)thiazolidine-4-one;

3-benzyl-2-(2-ethoxyphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;

N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}acetamide;

3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzamide;

3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoicacid, methyl ester;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(pyridin-3-ylimino)-thiazolidine-4-one;

N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethoxyphenyl}acetamide;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(pyridin-4-ylimino)thiazolidine-4-one;

4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoicacid, methyl ester;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-[4-(trifluoromethoxy)phenylimino]thiazolidine-4-one;

3-benzyl-2-(1H-indazol-5-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one;

3-benzyl-2-(4-imidazol-1-ylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;

2-(benzo[1,3]dioxol-5-ylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one;

3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoicacid;

3-benzyl-2-[2-(ethylamino)phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one;

3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(methylamino)benzonitrile;

3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(ethylamino)benzonitrile;

3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(isopropylamino)benzonitrile;

3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(dimethylamino)benzonitrile;

3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(tert-butylamino)benzonitrile;

3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(2,2,2-trifluoroethylamino)benzonitrile;

3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-piperidin-1-ylbenzonitrile;

2-[5-acetyl-2-(ethylamino)phenylimino]-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one;

3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-6-ylimino)thiazolidin-4-one;

3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-morpholin4-ylphenylimino)thiazolidin-4-one;

3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(methylamino)benzonitrile;

4-dimethylamino-3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile;

3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(isopropylamino)benzonitrile;

3-[3-butyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile;

3-benzyl-5-(3-methyl-3H-benzoxazol-2-ylidene)-2-(quinolin-5-ylimino)thiazolidin-4-one;

N-[4-(3′-benzyl-3-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]-bithiazolyliden-2′-ylideneamino)phenyl]acetamide;

2′-[5-acetyl-2-(ethylamino)phenylimino]-3′-benzyl-3-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one;

3-(3′-benzyl-3-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazol-yliden-2′-ylideneamino)-4-(ethylamino)benzonitrile;

N-[4-(3′-benzyl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)phenyl]acetamide;

N-[4-(3′-benzyl-3-methyl-4′-oxo-[2,5′]bithiazolidinyliden-2′-ylideneamino)phenyl]acetamide;

3-(3′-benzyl-3,5-dimethyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-(ethylamino)benzonitrile;

4-ethylamino-3-[3-benzyl-5-(3-methyl-5-chloro-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

3-phenyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-cyclohexylphenyl)imino-thiazolidine-4-one;

3-allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-hydroxy-1-naphthyl)imino-thiazolidine-4-one;

4-ethylamino-3-[3-phenyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(3-methyl-5-methoxy-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

3-allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(5-quinolyl)imino-thiazolidine-4-one;

4-ethylamino-3-[3-allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

3-phenyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-benzylimino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(8-quinolyl)imino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(8-hydroxy-5-quinolyl)imino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(5-isoquinolyl)imino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(1-isoquinolyl)imino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-methylcarbonylamino)phenylimino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-methylcarbonyl)phenylimino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-aminocarbonyl)phenylimino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(1-naphthyl)imino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-naphthyl)imino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-pyridyl)imino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-aminosulfonyl)phenylimino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-methylcarbonylaminosulfonyl)phenylimino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(3-methylcarbonyl)phenylimino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-methylcarbonylamino-5-pyridyl)imino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-cyano-5-methylcarbonylaminophenyl)imino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-methylcarbonylphenyl)imino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-methylamino-5-methylcarbonylphenyl)imino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-trifluoromethylcarbonylaminophenyl)imino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-methoxycarbonylphenyl)imino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-hydroxycarbonylphenyl)imino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-tert-butoxycarbonylphenyl)imino-thiazolidine-4-one;

4-butylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-benzylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-cyclopentylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-pyrrolidinylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-pyrrolidinyl-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-cyclohexyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

3-allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-hydroxy-2-methyl-5-isopropylphenyl)imino-thiazolidine-4-one;

3-cyclohexyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-hydroxy-1-naphthyl)imino-thiazolidine-4-one;

4-ethylamino-3-[3-benzyl-5-(6-fluoro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(6-ethoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(6-nitro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(5-trifluoromethyl-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(6-methylcarbonylamino-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(5-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(6-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(5-ethylaminocarbonyloxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(5-methoxycarbonylmethoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(5-aminocarbonylmethoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(5-(2-hydroxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(4-methoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(4-methyl-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(4-chloro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(5-(2-chloroethylaminocarbonyloxy)-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(5-(2-methylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-propyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

3-(3-pyridylmethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(3-acetylphenyl)imino-thiazolidine-4-one;

3-(3-pyridylmethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one;

4-ethylamino-3-[3-(3-pyridylmethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-(2-furylmethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

3-(4-methoxycarbonylbenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one;

3-(4-hydroxycarbonylbenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one;

4-ethylamino-3-[3-(2-phenylethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-(2-(4-morpholinyl)-1-ethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

3-benzyl-5-(3-methylthiazolin-2-ylidene)-2-(4-methylcarbonylaminophenyl)imino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-4-phenylthiazol-2-ylidene)-2-(4-methylcarbonylaminophenyl)imino-thiazolidine-4-one;

3-benzyl-5-(3-methyl-4-phenylthiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one;

3-benzyl-5-(3-methylthiazol-2-ylidene)-2-(4-methylcarbonylaminophenyl)imino-thiazolidine-4-one;

4-ethylamino-3-[3-benzyl-5-(3-methyl-4-phenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(3-methyl-4,5-dimethylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(3-methyl-4-phenyl-5-methylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(3-methyl-4,5-butylenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(3-methyl-4-ethylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-nitrophenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-fluorophenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-chlorophenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-methylphenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-methoxyphenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(3-methyl-4-methyl-5-acetylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(3-methyl-4,5-propylenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(3-methyl-4,5-diphenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-benzyl-5-(3-methyl-4-methylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;

4-ethylamino-3-[3-(3-pyridylmethyl)-5-(3-methyl-4,5-butylenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile;and

3-(4-methoxycarbonylbenzyl)-5-(3-methyl-4,5-butylenyl]thiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one.

In certain embodiments herein, the compounds provided herein are FXR orLXR antagonists. In these embodiments, the compounds have formulae I,where A and G are each independently substituted or unsubstitutedphenyl, substituted or unsubstituted naphthyl, or substituted orunsubstituted methyl, substituted or unsubstituted ethyl or togetherform substituted or unsubstituted butadienylene where there are 0 to 4substituents, in one embodiment 0 or 1 substituents, selected frommethylcarbonylamino, hydroxy, trifluoromethoxy, trifluorocarbonylamino,aminocarbonylmethoxy, 2-hydroxyethoxy, 3-hydroxypropoxy,dimethylaminocarbonyloxy, 2-(1-piperidinyl)ethoxy,2-(4-(1-methylpiperazin)yl)ethoxy, 2-(4-morpholinyl)ethoxy,2-dimethylaminoethoxy and hydroxycarbonylmethoxy; D and E form a bond;X¹ and X² are both S; X³ is O; R¹ is methyl; R² is benzyl; and R³ is5-cyano-2-ethylaminophenyl.

In certain embodiments, FXR or LXR antagonists provided herein areselected from the following compounds. All isomer of these compounds arewithin the scope of the disclosure herein:

3-(3′-Benzyl-3,5-dimethyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylamino-benzonitrile;

3-(3′-Benzyl-5-ethyl-3-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylamino-benzonitrile;

3-(3′-Benzyl-3-methyl-4-naphthalen-2-yl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylamino-benzonitrile;

3-[3′-Benzyl-4-(4-bromophenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylamino-benzonitrile;

3-[3′-Benzyl-4-(2-methoxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylamino-benzonitrile;

3-[3′-Benzyl-4-(3-fluorophenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylamino-benzonitrile;

3-[3′-Benzyl-4-(2,4-dimethoxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylamino-benzonitrile;

N-{2-[3-Benzyl-2-(5-cyano-2-ethylamino-phenylimino)-4-oxo-thiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-acetamide;

3-[3-Benzyl-5-(6-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]-4-ethylamino-benzonitrile;

3-[3-Benzyl-5-(3-methyl-6-trifluoromethoxy-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]-4-ethylamino-benzonitrile;

N-{2-[3-Benzyl-2-(5-cyano-2-ethylamino-phenylimino)-4-oxo-thiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-2,2,2-trifluoroacetamide;

2-{2-[3-Benzyl-2-(5-cyano-2-ethylamino-phenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yloxy}-acetamide;

3-{3-Benzyl-5-[5-(2-hydroxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylamino-benzonitrile;

3-{3-Benzyl-5-[5-(3-hydroxypropoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylamino-benzonitrile;

Dimethylcarbamic acid2-[3-benzyl-2-(5-cyano-2-ethylamino-phenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-ylester;

3-{3-Benzyl-5-[3-methyl-5-(2-piperidin-1-ylethoxy)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylamino-benzonitrile;

3-(3-Benzyl-5-{3-methyl-5-[2-(4-methylpiperazin-1-yl)-ethoxy]-3H-benzothiazol-2-ylidene}-4-oxothiazolidin-2-ylideneamino)-4-ethylamino-benzonitrile;

3-{3-Benzyl-5-[3-methyl-5-(2-morpholin-4-ylethoxy)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylamino-benzonitrile;

3-{3-Benzyl-5-[5-(2-dimethylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylamino-benzonitrile;and

{2-[3-Benzyl-2-(5-cyano-2-ethylamino-phenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yloxy}-aceticacid.

In another embodiment, the compounds for use in the compositions andmethods provided herein are shown in the Examples. All isomers of thesecompounds are within the scope of this disclosure.

C. Preparation of the Compounds

Starting materials in the synthesis examples provided herein are eitheravailable from commercial sources or via literature procedures. Allcommercially available compounds were used without further purificationunless otherwise indicated. CDCl₃ (99.8% D, Cambridge IsotopeLaboratories) was used in all experiments as indicated. Proton (¹H)nuclear magnetic resonance (NMR) spectra were recorded on a BrukerAvance 400 MHz NMR spectrometer. Significant peaks are tabulated andtypically include: number of protons, and multiplicity (s, singlet; d,double; t, triplet; q, quartet; m, multiplet; br s, broad singlet).Chemical shifts are reported as parts per million (δ) relative totetramethylsilane. Low-resolution mass spectra (MS) were obtained aselectrospray ionization (ESI) mass spectra, which were recorded on aPerkin-Elmer SCIEX HPLC/MS instrument using reverse-phase conditions(acetonitrile/water, 0.05% trifluoroacetic acid). Flash chromatographywas performed using Merck Silica Gel 60 (230-400 mesh) followingstandard protocol (Still et al. (1978) J. Org. Chem. 43, 2923).

The following illustrations depict general preparations of compoundsclaimed herein and consist of reactions typically known to one skilledin the art of chemical synthesis. The substituents A, D, E, G, R¹-R³ andX¹-X³ have been previously described. Also it will be apparent to oneskilled in the art that many of the products could exist as one or moreisomers, that is E/Z isomers, enantiomers and/or diastereomers.

As shown above, treatment of 2-(alkylthio)azole (1) with an alkylatingagent (R¹X) affords the corresponding 2-(alkylthio)azolium complex (2),which then is condensed with 2-iminoazolidine (3) in the presence of abase to yield heterocycle (4). Thus, for example, when 1 is a1,3-heterocycle such as thiazole (X¹=S; E and D form a bond) that isalkylated with methyl p-toluenesulfonate, an intermediate N-methylthiazolium complex 2 is prepared (see, e.g., U.S. Pat. Nos. 5,707,794and 2,388,963). Subsequently, for example, when 3 is an2-iminothiazolidinone (X²=S and X³=O), an2-imino-5-(thiazol-2-ylidene)thiazolidin-4-one 4 is generated. Likewise,other heterocycles 1, such as but not limited to thiazoles, thiazolines,benzimidazoles, benzoxazoles, quinolines, pyridines and indoles, shouldundergo this transformation when bearing a 2-alkylthio or 2-mercaptosubstituent.

The synthesis of intermediate 2 is alternatively prepared from thecorresponding thione precursor (5) upon alkylation with RX. For example,when 5 is thiazolin-2-thione (X¹=S) that is alkylated with methylp-toluenesulfonate (RX), an intermediate N-alkyl2-(thiomethyl)thiazolinium complex 2 is generated.

Furthermore, for example, when the thione precursor 5 isthiazole-2-thione (X¹=S; E and D form a bond), it can be prepared by thecondensation of a dithiocarbamate salt (X¹=S) with a α-haloketone, asdepicted below (see, e.g., Bellec et al. (1999) Chem. Mater. 11:3147;Humphlett et al. (1964) J. Org. Chem. 29:2146). Various dithiocarbamatesalts are synthesized, for example, by reacting a primary amine, e.g.,methylamine, with carbon disulfide in the presence of a base such asEt₃N (see, e.g., Humphlett et al. (1964) J. Org. Chem. 29:2146). Thethiazole-2-thione 5 can then be transformed into the correspondingthiazolium complex 2.

Alternatively, as depicted below, reaction of intermediate 2 withazolidin-2-thione (6) in the presence of base gives anotherazolidin-2-thione (7). Treatment of intermediate 7 with an alkylatingagent (RX) affords the 2-(alkylthio)azolium complex (8), which reactswith an amine in the presence of base to yield heterocycle 4. Thus, forexample, when 6 is a 1,3-heterocycle such as rhodanine (X²=S and X³=O)that is condensed with an intermediate N-methyl benzothiazolium complex2 (X¹=S; E and D form a bond; A and G form a fused benzene), a5-(benzothiazol-2-ylidene)thiazolidin-4-one-2-thione 7 is generated(see, e.g., U.S. Pat. Nos. 5,618,831 and 2,454,629). Subsequentlyintermediate 7 is alkylated with, for example, methyl p-toluenesulfonateto give a 5-(benzothiazol-2-ylidene)-2-methylthio-4-oxothiazolidiniumcomplex 8, which can react with, for example, an aniline to yield an2-imino-5-(benzothiazol-2-ylidene)thiazolidin-4-one 4 (see, e.g., U.S.Pat. No. 5,618,831).

In general, 2-iminoazolidines 3 may be prepared as depicted below. Thus,for example, when 3 is an 2-imino-4-thiazolidinone (X²=S and X³=O), itcan be prepared by condensing a thiourea (X²=S) with a 2-haloester(X³=O) in the presence of base, in which R³ is typically aryl orheteroaryl (see, e.g., Seada et al. (1993) Indian J. Heterocycl. Chem.3:81; and International Patent Application Publication No. WO 00/42031).

Likewise 2-iminoazolidines 3 may be prepared from a carbodiimide asdepicted below. For example, when 3 is an 2-imino-4-imidazolidinone(X²=NR and X³=O), it can be prepared by reacting a carbodiimide with a2-aminoester (X²=NR and X³=O). Also an 2-imino-4-oxazolidinones (X² andX³=O) can be prepared from a carbodiimide and a 2-hydroxyester.

Similarly azolidine-2-thiones 6 may be prepared as depicted below. Thus,for example, when 6 is a rhodanine (X²=S and X³=O), it can be preparedby condensing an isothiocyanate with a 2-mercaptoester (see, e.g., Doganet al. (1992) Tetrahedron 48:7157; and Drobnica et al. (1972) Chem.Zvesti 26:538). Also imidazolidin-4-one-2-thiones (X²=NR and X³=O) oroxazolidin-4-one-2-thiones (X² and X³=O) can be prepared by reacting anisothiocyanate with 2-aminoester or 2-hydroxyester, respectively.

Alkyl and aryl isothiocyanates, aryl amines, rhodanines, unsymmetricalcarbodiimides and thioureas may be synthesized utilizing knownmethodology (see, e.g., Katritzky et al. (1984) ComprehensiveHeterocyclic Chemistry; Pergamon Press: Oxford, UK; Katritzky et al.(2000) Handbook of Heterocyclic Chemistry, 2^(nd) Ed.; Pergamon Press:Oxford, UK; March Advanced Organic Chemistry, 4^(th) Ed.; John Wiley:New York (1992); and International Patent Application Publication No. WO00/42031). For example, alkyl and aryl isothiocyanates are readilyprepared from reaction of an amine with thiophosgene or a thiophosgeneequivalent, e.g. thiocarbonyl diimidazole. Many isothiocyanates also arecommercially available. Unsymmetrical thioureas are prepared fromreaction of an isothiocyanate with an amine.

D. Formulation of Pharmaceutical Compositions

The pharmaceutical compositions provided herein contain therapeuticallyeffective amounts of one or more of the nuclear receptor activitymodulators provided herein that are useful in the prevention, treatment,or amelioration of one or more of the symptoms of diseases or disordersassociated with nuclear receptor activity, including FXR, LXR and/ororphan nuclear receptor activity. Such diseases or disorders include,but are not limited to, hypercholesterolemia, hyperlipoproteinemia,hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus,dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris,acneiform skin conditions, diabetes, Parkinson's disease, cancer,Alzheimer's disease, inflammation, immunological disorders, lipiddisorders, obesity, conditions characterized by a perturbed epidermalbarrier function, hyperlipidemia, cholestasis, peripheral occlusivedisease, ischemic stroke, conditions of disturbed differentiation orexcess proliferation of the epidermis or mucous membrane, andcardiovascular disorders.

The compositions contain one or more compounds provided herein. Thecompounds are preferably formulated into suitable pharmaceuticalpreparations such as solutions, suspensions, tablets, dispersibletablets, pills, capsules, powders, sustained release formulations orelixirs, for oral administration or in sterile solutions or suspensionsfor parenteral administration, as well as transdermal patch preparationand dry powder inhalers. Typically the compounds described above areformulated into pharmaceutical compositions using techniques andprocedures well known in the art (see, e.g., Ansel Introduction toPharmaceutical Dosage Forms, Fourth Edition 1985, 126).

In the compositions, effective concentrations of one or more compoundsor pharmaceutically acceptable derivatives is (are) mixed with asuitable pharmaceutical carrier or vehicle. The compounds may bederivatized as the corresponding salts, esters, enol ethers or esters,acids, bases, solvates, hydrates or prodrugs prior to formulation, asdescribed above. The concentrations of the compounds in the compositionsare effective for delivery of an amount, upon administration, thattreats, prevents, or ameliorates one or more of the symptoms of diseasesor disorders associated with nuclear receptor activity or in whichnuclear receptor activity is implicated. Such diseases or disordersinclude, but are not limited to, hypercholesterolemia,hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy,hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis,gallstone disease, acne vulgaris, acneiform skin conditions, diabetes,Parkinson's disease, cancer, Alzheimer's disease, inflammation,immunological disorders, lipid disorders, obesity, conditionscharacterized by a perturbed epidermal barrier function, hyperlipidemia,cholestasis, peripheral occlusive disease, ischemic stroke, conditionsof disturbed differentiation or excess proliferation of the epidermis ormucous membrane, and cardiovascular disorders.

Typically, the compositions are formulated for single dosageadministration. To formulate a composition, the weight fraction ofcompound is dissolved, suspended, dispersed or otherwise mixed in aselected vehicle at an effective concentration such that the treatedcondition is relieved or ameliorated. Pharmaceutical carriers orvehicles suitable for administration of the compounds provided hereininclude any such carriers known to those skilled in the art to besuitable for the particular mode of administration.

In addition, the compounds may be formulated as the solepharmaceutically active ingredient in the composition or may be combinedwith other active ingredients. Liposomal suspensions, includingtissue-targeted liposomes, such as tumor-targeted liposomes, may also besuitable as pharmaceutically acceptable carriers. These may be preparedaccording to methods known to those skilled in the art. For example,liposome formulations may be prepared as described in U.S. Pat. No.4,522,811. Briefly, liposomes such as multilamellar vesicles (MLV's) maybe formed by drying down egg phosphatidyl choline and brain phosphatidylserine (7:3 molar ratio) on the inside of a flask. A solution of acompound provided herein in phosphate buffered saline lacking divalentcations (PBS) is added and the flask shaken until the lipid film isdispersed. The resulting vesicles are washed to remove unencapsulatedcompound, pelleted by centrifugation, and then resuspended in PBS.

The active compound is included in the pharmaceutically acceptablecarrier in an amount sufficient to exert a therapeutically useful effectin the absence of undesirable side effects on the patient treated. Thetherapeutically effective concentration may be determined empirically bytesting the compounds in in vitro and in vivo systems described hereinand in International Patent Application Publication Nos. 99/27365 and00/25134 (see, e.g., EXAMPLES 53 and 54) and then extrapolated therefromfor dosages for humans.

The concentration of active compound in the pharmaceutical compositionwill depend on absorption, inactivation and excretion rates of theactive compound, the physicochemical characteristics of the compound,the dosage schedule, and amount administered as well as other factorsknown to those of skill in the art. For example, the amount that isdelivered is sufficient to ameliorate one or more of the symptoms ofdiseases or disorders associated with nuclear receptor activity or inwhich nuclear receptor activity is implicated, as described herein.

Typically a therapeutically effective dosage should produce a serumconcentration of active ingredient of from about 0.1 ng/ml to about50-100 μg/ml. The pharmaceutical compositions typically should provide adosage of from about 0.001 mg to about 2000 mg of compound per kilogramof body weight per day. Pharmaceutical dosage unit forms are prepared toprovide from about 1 mg to about 1000 mg and preferably from about 10 toabout 500 mg of the essential active ingredient or a combination ofessential ingredients per dosage unit form.

The active ingredient may be administered at once, or may be dividedinto a number of smaller doses to be administered at intervals of time.It is understood that the precise dosage and duration of treatment is afunction of the disease being treated and may be determined empiricallyusing known testing protocols or by extrapolation from in vivo or invitro test data. It is to be noted that concentrations and dosage valuesmay also vary with the severity of the condition to be alleviated. It isto be further understood that for any particular subject, specificdosage regimens should be adjusted over time according to the individualneed and the professional judgment of the person administering orsupervising the administration of the compositions, and that theconcentration ranges set forth herein are exemplary only and are notintended to limit the scope or practice of the claimed compositions.

Pharmaceutically acceptable derivatives include acids, bases, enolethers and esters, salts, esters, hydrates, solvates and prodrug forms.The derivative is selected such that its pharmacokinetic properties aresuperior to the corresponding neutral compound.

Thus, effective concentrations or amounts of one or more of thecompounds described herein or pharmaceutically acceptable derivativesthereof are mixed with a suitable pharmaceutical carrier or vehicle forsystemic, topical or local administration to form pharmaceuticalcompositions. Compounds are included in an amount effective forameliorating one or more symptoms of, or for treating or preventingdiseases or disorders associated with nuclear receptor activity or inwhich nuclear receptor activity is implicated, as described herein. Theconcentration of active compound in the composition will depend onabsorption, inactivation, excretion rates of the active compound, thedosage schedule, amount administered, particular formulation as well asother factors known to those of skill in the art.

The compositions are intended to be administered by a suitable route,including orally, parenterally, rectally, topically and locally. Fororal administration, capsules and tablets are presently preferred. Thecompositions are in liquid, semi-liquid or solid form and are formulatedin a manner suitable for each route of administration. Preferred modesof administration include parenteral and oral modes of administration.Oral administration is presently most preferred.

Solutions or suspensions used for parenteral, intradermal, subcutaneous,or topical application can include any of the following components: asterile diluent, such as water for injection, saline solution, fixedoil, polyethylene glycol, glycerine, propylene glycol or other syntheticsolvent; antimicrobial agents, such as benzyl alcohol and methylparabens; antioxidants, such as ascorbic acid and sodium bisulfite;chelating agents, such as ethylenediaminetetraacetic acid (EDTA);buffers, such as acetates, citrates and phosphates; and agents for theadjustment of tonicity such as sodium chloride or dextrose. Parenteralpreparations can be enclosed in ampules, disposable syringes or singleor multiple dose vials made of glass, plastic or other suitablematerial.

In instances in which the compounds exhibit insufficient solubility,methods for solubilizing compounds may be used. Such methods are knownto those of skill in this art, and include, but are not limited to,using cosolvents, such as dimethylsulfoxide (DMSO), using surfactants,such as TWEEN®, or dissolution in aqueous sodium bicarbonate.Derivatives of the compounds, such as prodrugs of the compounds may alsobe used in formulating effective pharmaceutical compositions.

Upon mixing or addition of the compound(s), the resulting mixture may bea solution, suspension, emulsion or the like. The form of the resultingmixture depends upon a number of factors, including the intended mode ofadministration and the solubility of the compound in the selectedcarrier or vehicle. The effective concentration is sufficient forameliorating the symptoms of the disease, disorder or condition treatedand may be empirically determined.

The pharmaceutical compositions are provided for administration tohumans and animals in unit dosage forms, such as tablets, capsules,pills, powders, granules, sterile parenteral solutions or suspensions,and oral solutions or suspensions, and oil-water emulsions containingsuitable quantities of the compounds or pharmaceutically acceptablederivatives thereof. The pharmaceutically therapeutically activecompounds and derivatives thereof are typically formulated andadministered in unit-dosage forms or multiple-dosage forms. Unit-doseforms as used herein refers to physically discrete units suitable forhuman and animal subjects and packaged individually as is known in theart. Each unit-dose contains a predetermined quantity of thetherapeutically active compound sufficient to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier, vehicle or diluent. Examples of unit-dose forms includeampoules and syringes and individually packaged tablets or capsules.Unit-dose forms may be administered in fractions or multiples thereof. Amultiple-dose form is a plurality of identical unit-dosage formspackaged in a single container to be administered in segregatedunit-dose form. Examples of multiple-dose forms include vials, bottlesof tablets or capsules or bottles of pints or gallons. Hence, multipledose form is a multiple of unit-doses which are not segregated inpackaging.

The composition can contain along with the active ingredient: a diluentsuch as lactose, sucrose, dicalcium phosphate, orcarboxymethylcellulose; a lubricant, such as magnesium stearate, calciumstearate and talc; and a binder such as starch, natural gums, such asgum acaciagelatin, glucose, molasses, polvinylpyrrolidine, cellulosesand derivatives thereof, povidone, crospovidones and other such bindersknown to those of skill in the art. Liquid pharmaceuticallyadministrable compositions can, for example, be prepared by dissolving,dispersing, or otherwise mixing an active compound as defined above andoptional pharmaceutical adjuvants in a carrier, such as, for example,water, saline, aqueous dextrose, glycerol, glycols, ethanol, and thelike, to thereby form a solution or suspension. If desired, thepharmaceutical composition to be administered may also contain minoramounts of nontoxic auxiliary substances such as wetting agents,emulsifying agents, or solubilizing agents, pH buffering agents and thelike, for example, acetate, sodium citrate, cyclodextrine derivatives,sorbitan monolaurate, triethanolamine sodium acetate, triethanolamineoleate, and other such agents. Actual methods of preparing such dosageforms are known, or will be apparent, to those skilled in this art; forexample, see Remington's Pharmaceutical Sciences, Mack PublishingCompany, Easton, Pa., 15th Edition, 1975. The composition or formulationto be administered will, in any event, contain a quantity of the activecompound in an amount sufficient to alleviate the symptoms of thetreated subject.

Dosage forms or compositions containing active ingredient in the rangeof 0.005% to 100% with the balance made up from non-toxic carrier may beprepared. For oral administration, a pharmaceutically acceptablenon-toxic composition is formed by the incorporation of any of thenormally employed excipients, such as, for example pharmaceutical gradesof mannitol, lactose, starch, magnesium stearate, talcum, cellulosederivatives, sodium crosscarmellose, glucose, sucrose, magnesiumcarbonate or sodium saccharin. Such compositions include solutions,suspensions, tablets, capsules, powders and sustained releaseformulations, such as, but not limited to, implants andmicroencapsulated delivery systems, and biodegradable, biocompatiblepolymers, such as collagen, ethylene vinyl acetate, polyanhydrides,polyglycolic acid, polyorthoesters, polylactic acid and others. Methodsfor preparation of these compositions are known to those skilled in theart. The contemplated compositions may contain 0.001%-100% activeingredient, preferably 0.1-85%, typically 75-95%.

The active compounds or pharmaceutically acceptable derivatives may beprepared with carriers that protect the compound against rapidelimination from the body, such as time release formulations orcoatings. The compositions may include other active compounds to obtaindesired combinations of properties. The compounds provided herein, orpharmaceutically acceptable derivatives thereof as described herein, mayalso be advantageously administered for therapeutic or prophylacticpurposes together with another pharmacological agent known in thegeneral art to be of value in treating one or more of the diseases ormedical conditions referred to hereinabove, such as diseases ordisorders associated with nuclear receptor activity or in which nuclearreceptor activity is implicated. It is to be understood that suchcombination therapy constitutes a further aspect of the compositions andmethods of treatment provided herein.

1. Compositions for Oral Administration

Oral pharmaceutical dosage forms are either solid, gel or liquid. Thesolid dosage forms are tablets, capsules, granules, and bulk powders.Types of oral tablets include compressed, chewable lozenges and tabletswhich may be enteric-coated, sugar-coated or film-coated. Capsules maybe hard or soft gelatin capsules, while granules and powders may beprovided in non-effervescent or effervescent form with the combinationof other ingredients known to those skilled in the art.

In certain embodiments, the formulations are solid dosage forms,preferably capsules or tablets. The tablets, pills, capsules, trochesand the like can contain any of the following ingredients, or compoundsof a similar nature: a binder; a diluent; a disintegrating agent; alubricant; a glidant; a sweetening agent; and a flavoring agent.

Examples of binders include microcrystalline cellulose, gum tragacanth,glucose solution, acacia mucilage, gelatin solution, sucrose and starchpaste. Lubricants include talc, starch, magnesium or calcium stearate,lycopodium and stearic acid. Diluents include, for example, lactose,sucrose, starch, kaolin, salt, mannitol and dicalcium phosphate.Glidants include, but are not limited to, colloidal silicon dioxide.Disintegrating agents include crosscarmellose sodium, sodium starchglycolate, alginic acid, corn starch, potato starch, bentonite,methylcellulose, agar and carboxymethylcellulose. Coloring agentsinclude, for example, any of the approved certified water soluble FD andC dyes, mixtures thereof; and water insoluble FD and C dyes suspended onalumina hydrate. Sweetening agents include sucrose, lactose, mannitoland artificial sweetening agents such as saccharin, and any number ofspray dried flavors. Flavoring agents include natural flavors extractedfrom plants such as fruits and synthetic blends of compounds whichproduce a pleasant sensation, such as, but not limited to peppermint andmethyl salicylate. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelaural ether. Emetic-coatings include fatty acids, fats, waxes, shellac,ammoniated shellac and cellulose acetate phthalates. Film coatingsinclude hydroxyethylcellulose, sodium carboxymethylcellulose,polyethylene glycol 4000 and cellulose acetate phthalate.

If oral administration is desired, the compound could be provided in acomposition that protects it from the acidic environment of the stomach.For example, the composition can be formulated in an enteric coatingthat maintains its integrity in the stomach and releases the activecompound in the intestine. The composition may also be formulated incombination with an antacid or other such ingredient.

When the dosage unit form is a capsule, it can contain, in addition tomaterial of the above type, a liquid carrier such as a fatty oil. Inaddition, dosage unit forms can contain various other materials whichmodify the physical form of the dosage unit, for example, coatings ofsugar and other enteric agents. The compounds can also be administeredas a component of an elixir, suspension, syrup, wafer, sprinkle, chewinggum or the like. A syrup may contain, in addition to the activecompounds, sucrose as a sweetening agent and certain preservatives, dyesand colorings and flavors.

The active materials can also be mixed with other active materials whichdo not impair the desired action, or with materials that supplement thedesired action′, such as antacids, H2 blockers, and diuretics. Theactive ingredient is a compound or pharmaceutically acceptablederivative thereof as described herein. Higher concentrations, up toabout 98% by weight of the active ingredient may be included.

Pharmaceutically acceptable carriers included in tablets are binders,lubricants, diluents, disintegrating agents, coloring agents, flavoringagents, and wetting agents. Enteric-coated tablets, because of theenteric-coating, resist the action of stomach acid and dissolve ordisintegrate in the neutral or alkaline intestines. Sugar-coated tabletsare compressed tablets to which different layers of pharmaceuticallyacceptable substances are applied. Film-coated tablets are compressedtablets which have been coated with a polymer or other suitable coating.Multiple compressed tablets are compressed tablets made by more than onecompression cycle utilizing the pharmaceutically acceptable substancespreviously mentioned. Coloring agents may also be used in the abovedosage forms. Flavoring and sweetening agents are used in compressedtablets, sugar-coated, multiple compressed and chewable tablets.Flavoring and sweetening agents are especially useful in the formationof chewable tablets and lozenges.

Liquid oral dosage forms include aqueous solutions, emulsions,suspensions, solutions and/or suspensions reconstituted fromnon-effervescent granules and effervescent preparations reconstitutedfrom effervescent granules. Aqueous solutions include, for example,elixirs and syrups. Emulsions are either oil-in-water or water-in-oil.

Elixirs are clear, sweetened, hydroalcoholic preparations.Pharmaceutically acceptable carriers used in elixirs include solvents.Syrups are concentrated aqueous solutions of a sugar, for example,sucrose, and may contain a preservative. An emulsion is a two-phasesystem in which one liquid is dispersed in the form of small globulesthroughout another liquid. Pharmaceutically acceptable carriers used inemulsions are non-aqueous liquids, emulsifying agents and preservatives.Suspensions use pharmaceutically acceptable suspending agents andpreservatives. Pharmaceutically acceptable substances used innon-effervescent granules, to be reconstituted into a liquid oral dosageform, include diluents, sweeteners and wetting agents. Pharmaceuticallyacceptable substances used in effervescent granules, to be reconstitutedinto a liquid oral dosage form, include organic acids and a source ofcarbon dioxide. Coloring and flavoring agents are used in all of theabove dosage forms.

Solvents include glycerin, sorbitol, ethyl alcohol and syrup. Examplesof preservatives include glycerin, methyl and propylparaben, benzoicadd, sodium benzoate and alcohol. Examples of non-aqueous liquidsutilized in emulsions include mineral oil and cottonseed oil. Examplesof emulsifying agents include gelatin, acacia, tragacanth, bentonite,and surfactants such as polyoxyethylene sorbitan monooleate. Suspendingagents include sodium carboxymethylcellulose, pectin, tragacanth, Veegumand acacia. Diluents include lactose and sucrose. Sweetening agentsinclude sucrose, syrups, glycerin and artificial sweetening agents suchas saccharin. Wetting agents include propylene glycol monostearate,sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylenelauryl ether. Organic adds include citric and tartaric acid. Sources ofcarbon dioxide include sodium bicarbonate and sodium carbonate. Coloringagents include any of the approved certified water soluble FD and Cdyes, and mixtures thereof. Flavoring agents include natural flavorsextracted from plants such fruits, and synthetic blends of compoundswhich produce a pleasant taste sensation.

For a solid dosage form, the solution or suspension, in for examplepropylene carbonate, vegetable oils or triglycerides, is preferablyencapsulated in a gelatin capsule. Such solutions, and the preparationand encapsulation thereof, are disclosed in U.S. Pat. Nos. 4,328,245;4,409,239; and 4,410,545. For a liquid dosage form, the solution, e.g.,for example, in a polyethylene glycol, may be diluted with a sufficientquantity of a pharmaceutically acceptable liquid carrier, e.g., water,to be easily measured for administration.

Alternatively, liquid or semi-solid oral formulations may be prepared bydissolving or dispersing the active compound or salt in vegetable oils,glycols, triglycerides, propylene glycol esters (e.g., propylenecarbonate) and other such carriers, and encapsulating these solutions orsuspensions in hard or soft gelatin capsule shells. Other usefulformulations include those set forth in U.S. Pat. Nos. Re 28,819 and4,358,603. Briefly, such formulations include, but are not limited to,those containing a compound provided herein, a dialkylated mono- orpoly-alkylene glycol, including, but not limited to,1,2-dimethoxymethane, diglyme, triglyme, tetraglyme, polyethyleneglycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether,polyethylene glycol-750-dimethyl ether wherein 350, 550 and 750 refer tothe approximate average molecular weight of the polyethylene glycol, andone or more antioxidants, such as butylated hydroxytoluene (BHT),butylated hydroxyanisole (BHA), propyl gallate, vitamin E, hydroquinone,hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malicacid, sorbitol, phosphoric acid, thiodipropionic acid and its esters,and dithiocarbamates.

Other formulations include, but are not limited to, aqueous alcoholicsolutions including a pharmaceutically acceptable acetal. Alcohols usedin these formulations are any pharmaceutically acceptable water-misciblesolvents having one or more hydroxyl groups, including, but not limitedto, propylene glycol and ethanol. Acetals include, but are not limitedto, di(lower alkyl) acetals of lower alkyl aldehydes such asacetaldehyde diethyl acetal.

In all embodiments, tablets and capsules formulations may be coated asknown by those of skill in the art in order to modify or sustaindissolution of the active ingredient. Thus, for example, they may becoated with a conventional enterically digestible coating, such asphenylsalicylate, waxes and cellulose acetate phthalate.

2. Injectables, Solutions and Emulsions

Parenteral administration, generally characterized by injection, eithersubcutaneously, intramuscularly or intravenously is also contemplatedherein. Injectables can be prepared in conventional forms, either asliquid solutions or suspensions, solid forms suitable for solution orsuspension in liquid prior to injection, or as emulsions. Suitableexcipients are, for example, water, saline, dextrose, glycerol orethanol. In addition, if desired, the pharmaceutical compositions to beadministered may also contain minor amounts of non-toxic auxiliarysubstances such as wetting or emulsifying agents, pH buffering agents,stabilizers, solubility enhancers, and other such agents, such as forexample, sodium acetate, sorbitan monolaurate, triethanolamine oleateand cyclodextrins. Implantation of a slow-release or sustained-releasesystem, such that a constant level of dosage is maintained (see, e.g.,U.S. Pat. No. 3,710,795) is also contemplated herein. Briefly, acompound provided herein is dispersed in a solid inner matrix, e.g.,polymethylmethacrylate, polybutylmethacrylate, plasticized orunplasticized polyvinylchloride, plasticized nylon, plasticizedpolyethyleneterephthalate, natural rubber, polyisoprene,polyisobutylene, polybutadiene, polyethylene, ethylene-vinylacetatecopolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonatecopolymers, hydrophilic polymers such as hydrogels of esters of acrylicand methacrylic acid, collagen, cross-linked polyvinylalcohol andcross-linked partially hydrolyzed polyvinyl acetate, that is surroundedby an outer polymeric membrane, e.g., polyethylene, polypropylene,ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers,ethylene/vinylacetate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, chlorinated polyethylene, polyvinylchloride,vinylchloride copolymers with vinyl acetate, vinylidene chloride,ethylene and propylene, ionomer polyethylene terephthalate, butyl rubberepichlorohydrin rubbers, ethylene/vinyl alcohol copolymer,ethylene/vinyl acetate/vinyl alcohol terpolymer, andethylene/vinyloxyethanol copolymer, that is insoluble in body fluids.The compound diffuses through the outer polymeric membrane in a releaserate controlling step. The percentage of active compound contained insuch parenteral compositions is highly dependent on the specific naturethereof, as well as the activity of the compound and the needs of thesubject.

Parenteral administration of the compositions includes intravenous,subcutaneous and intramuscular administrations. Preparations forparenteral administration include sterile solutions ready for injection,sterile dry soluble products, such as lyophilized powders, ready to becombined with a solvent just prior to use, including hypodermic tablets,sterile suspensions ready for injection, sterile dry insoluble productsready to be combined with a vehicle just prior to use and sterileemulsions. The solutions may be either aqueous or nonaqueous.

If administered intravenously, suitable carriers include physiologicalsaline or phosphate buffered saline (PBS), and solutions containingthickening and solubilizing agents, such as glucose, polyethyleneglycol, and polypropylene glycol and mixtures thereof.

Pharmaceutically acceptable carriers used in parenteral preparationsinclude aqueous vehicles, nonaqueous vehicles, antimicrobial agents,isotonic agents, buffers, antioxidants, local anesthetics, suspendingand dispersing agents, emulsifying agents, sequestering or chelatingagents and other pharmaceutically acceptable substances.

Examples of aqueous vehicles include Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose and Lactated Ringers Injection. Nonaqueous parenteral vehiclesinclude fixed oils of vegetable origin, cottonseed oil, corn oil, sesameoil and peanut oil. Antimicrobial agents in bacteriostatic orfungistatic concentrations must be added to parenteral preparationspackaged in multiple-dose containers which include phenols or cresols,mercurials, benzyl alcohol, chlorobutanol, methyl and propylp-hydroxybenzoic acid esters, thimerosal, benzalkonium chloride andbenzethonium chloride. Isotonic agents include sodium chloride anddextrose. Buffers include phosphate and citrate. Antioxidants includesodium bisulfate. Local anesthetics include procaine hydrochloride.Suspending and dispersing agents include sodium carboxymethylcelluose,hydroxypropyl methylcellulose and polyvinylpyrrolidone. Emulsifyingagents include Polysorbate 80 (TWEEN® 80). A sequestering or chelatingagent of metal ions include EDTA. Pharmaceutical carriers also includeethyl alcohol, polyethylene glycol and propylene glycol for watermiscible vehicles and sodium hydroxide, hydrochloric acid, citric acidor lactic acid for pH adjustment.

The concentration of the pharmaceutically active compound is adjusted sothat an injection provides an effective amount to produce the desiredpharmacological effect. The exact dose depends on the age, weight andcondition of the patient or animal as is known in the art.

The unit-dose parenteral preparations are packaged in an ampoule, a vialor a syringe with a needle. All preparations for parenteraladministration must be sterile, as is known and practiced in the art.

Illustratively, intravenous or intraarterial infusion of a sterileaqueous solution containing an active compound is an effective mode ofadministration. Another embodiment is a sterile aqueous or oily solutionor suspension containing an active material injected as necessary toproduce the desired pharmacological effect.,

Injectables are designed for local and systemic administration.Typically a therapeutically effective dosage is formulated to contain aconcentration of at least about 0.1% w/w up to about 90% w/w or more,preferably more than 1% w/w of the active compound to the treatedtissue(s). The active ingredient may be administered at once, or may bedivided into a number of smaller doses to be administered at intervalsof time. It is understood that the precise dosage and duration oftreatment is a function of the tissue being treated and may bedetermined empirically using known testing protocols or by extrapolationfrom in vivo or in vitro test data. It is to be noted thatconcentrations and dosage values may also vary with the age of theindividual treated. It is to be further understood that for anyparticular subject, specific dosage regimens should be adjusted overtime according to the individual need and the professional judgment ofthe person administering or supervising the administration of theformulations, and that the concentration ranges set forth herein areexemplary only and are not intended to limit the scope or practice ofthe claimed formulations.

The compound may be suspended in micronized or other suitable form ormay be derivatized to produce a more soluble active product or toproduce a prodrug. The form of the resulting mixture depends upon anumber of factors, including the intended mode of administration and thesolubility of the compound in the selected carrier or vehicle. Theeffective concentration is sufficient for ameliorating the symptoms ofthe condition and may be empirically determined.

3. Lyophilized Powders

Of interest herein are also lyophilized powders, which can bereconstituted for administration as solutions, emulsions and othermixtures. They may also be reconstituted and formulated as solids orgels.

The sterile, lyophilized powder is prepared by dissolving a compoundprovided herein, or a pharmaceutically acceptable derivative thereof, ina suitable solvent. The solvent may contain an excipient which improvesthe stability or other pharmacological component of the powder orreconstituted solution, prepared from the powder. Excipients that may beused include, but are not limited to, dextrose, sorbital, fructose, cornsyrup, xylitol, glycerin, glucose, sucrose or other suitable agent. Thesolvent may also contain a buffer, such as citrate, sodium or potassiumphosphate or other such buffer known to those of skill in the art at,typically, about neutral pH. Subsequent sterile filtration of thesolution followed by lyophilization under standard conditions known tothose of skill in the art provides the desired formulation. Generally,the resulting solution will be apportioned into vials forlyophilization. Each vial will contain a single dosage (10-1000 mg,preferably 100-500 mg) or multiple dosages of the compound. Thelyophilized powder can be stored under appropriate conditions, such asat about 4° C. to room temperature.

Reconstitution of this lyophilized powder with water for injectionprovides a formulation for use in parenteral administration. Forreconstitution, about 1-50 mg, preferably 5-35 mg, more preferably about9-30 mg of lyophilized powder, is added per mL of sterile water or othersuitable carrier. The precise amount depends upon the selected compound.Such amount can be empirically determined.

4. Topical Administration

Topical mixtures are prepared as described for the local and systemicadministration. The resulting mixture may be a solution, suspension,emulsions or the like and are formulated as creams, gels, ointments,emulsions, solutions, elixirs, lotions, suspensions, tinctures, pastes,foams, aerosols, irrigations, sprays, suppositories, bandages, dermalpatches or any other formulations suitable for topical administration.

The compounds or pharmaceutically acceptable derivatives thereof may beformulated as aerosols for topical application, such as by inhalation(see, e.g., U.S. Pat. Nos. 4,044,126, 4,414,209, and 4,364,923, whichdescribe aerosols for delivery of a steroid useful for treatment ofinflammatory diseases, particularly asthma). These formulations foradministration to the respiratory tract can be in the form of an aerosolor solution for a nebulizer, or as a microfine powder for insufflation,alone or in combination with an inert carrier such as lactose. In such acase, the particles of the formulation will typically have diameters ofless than 50 microns, preferably less than 10 microns.

The compounds may be formulated for local or topical application, suchas for topical application to the skin and mucous membranes, such as inthe eye, in the form of gels, creams, and lotions and for application tothe eye or for intracisternal or intraspinal application. Topicaladministration is contemplated for transdermal delivery and also foradministration to the eyes or mucosa, or for inhalation therapies. Nasalsolutions of the active compound alone or in combination with otherpharmaceutically acceptable excipients can also be administered.

These solutions, particularly those intended for ophthalmic use, may beformulated as 0.01%-10% isotonic solutions, pH about 5-7, withappropriate salts.

5. Compositions for Other Routes of Administration

Other routes of administration, such as topical application, transdermalpatches, and rectal administration are also contemplated herein.

For example, pharmaceutical dosage forms for rectal administration arerectal suppositories, capsules and tablets for systemic effect. Rectalsuppositories are used herein mean solid bodies for insertion into therectum which melt or soften at body temperature releasing one or morepharmacologically or therapeutically active ingredients.Pharmaceutically acceptable substances utilized in rectal suppositoriesare bases or vehicles and agents to raise the melting point. Examples ofbases include cocoa butter (theobroma oil), glycerin-gelatin, carbowax(polyoxyethylene glycol) and appropriate mixtures of mono-, di- andtriglycerides of fatty acids. Combinations of the various bases may beused. Agents to raise the melting point of suppositories includespermaceti and wax. Rectal suppositories may be prepared either by thecompressed method or by molding. The typical weight of a rectalsuppository is about 2 to 3 gm.

Tablets and capsules for rectal administration are manufactured usingthe same pharmaceutically acceptable substance and by the same methodsas for formulations for oral administration.

6. Articles of Manufacture

The compounds or pharmaceutically acceptable derivatives may be packagedas articles of manufacture containing packaging material, a compound orpharmaceutically acceptable derivative thereof provided herein, which iseffective for modulating the activity of nuclear receptors, includingFXR, LXR and/or orphan nuclear receptors, or for treatment, preventionor amelioration of one or more symptoms of nuclear receptor, includingFXR, LXR and/or orphan nuclear receptor, mediated diseases or disorders,or diseases or disorders in which nuclear receptor activity, includingFXR, LXR and/or orphan nuclear receptor activity, is implicated, withinthe packaging material, and a label that indicates that the compound orcomposition, or pharmaceutically acceptable derivative thereof, is usedfor modulating the activity of nuclear receptors, including FXR, LXRand/or orphan nuclear receptors, or for treatment, prevention oramelioration of one or more symptoms of nuclear receptor, including FXR,LXR and/or orphan nuclear receptor, mediated diseases or disorders, ordiseases or disorders in which nuclear receptor activity, including FXR,LXR and/or orphan nuclear receptor activity, is implicated.

The articles of manufacture provided herein contain packaging materials.Packaging materials for use in packaging pharmaceutical products arewell known to those of skill in the art. See, e.g., U.S. Pat. Nos.5,323,907, 5,052,558 and 5,033,252. Examples of pharmaceutical packagingmaterials include, but are not limited to, blister packs, bottles,tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, andany packaging material suitable for a selected formulation and intendedmode of administration and treatment. A wide array of formulations ofthe compounds and compositions provided herein are contemplated as are avariety of treatments for any disease or disorder in which nuclearreceptor activity, including FXR, LXR and/or orphan nuclear receptoractivity, is implicated as a mediator or contributor to the symptoms orcause.

E. Evaluation of the Activity of the Compounds

Standard physiological, pharmacological and biochemical procedures areavailable for testing the compounds to identify those that possessbiological activities that modulate the activity or nuclear receptors,including the FXR. Such assays include, for example, biochemical assayssuch as binding assays, fluorescence polarization assays, FRET basedcoactivator recruitment assays (see generally Glickman et al., J.Biomolecular Screening, 7 No. 13-10 (2002)), as well as cell basedassays including the co-transfection assay, the use of LBD-Gal 4chimeras and protein-protein interaction assays (see, Lehmann. et al.,J. Biol Chem., 272(6) 3137-3140 (1997).

High throughput screening systems are commercially available (see, e.g.,Zymark Corp., Hopkinton, Mass.; Air Technical Industries, Mentor, Ohio;Beckman Instruments Inc., Fullerton, Calif.; Precision Systems, Inc.,Natick, Mass.) that enable these assays to be run in a high throughputmode. These systems typically automate entire procedures, including allsample and reagent pipetting, liquid dispensing timed incubations, andfinal readings of the microplate in detector(s) appropriate for theassay. These configurable systems provide high throughput and rapidstart up as well as a high degree of flexibility and customization. Themanufacturers of such systems provide detailed protocols for varioushigh throughput systems. Thus, for example, Zymark Corp. providestechnical bulletins describing screening systems for detecting themodulation of gene transcription, ligand binding, and the like.

Assays that do not require washing or liquid separation steps arepreferred for such high throughput screening systems and includebiochemical assays such as fluorescence polarization assays (see forexample, Owicki, J., Biomol Screen 2000 October;5(5):297) scintillationproximity assays (SPA) (see for example, Carpenter et al., Methods MolBiol 2002; 190:31-49) and fluorescence resonance energy transfer energytransfer (FRET) or time resolved FRET based coactivator recruitmentassays (Mukherjee et al., J Steroid Biochem Mol Biol 2002July;81(3):217-25; (Zhou et al., Mol Endocrinol. 1998 October;12(10):1594-604). Generally such assays can be preformed using eitherthe full length receptor, or isolated ligand binding domain (LBD). Inthe case of FXR, the LBD comprises amino acids 244 to 472 of the fulllength sequence.

If a fluorescently labeled ligand is available, fluorescencepolarization assays provide a way of detecting binding of compounds tothe nuclear receptor of interest by measuring changes in fluorescencepolarization that occur as a result of the displacement of a traceamount of the label ligand by the compound. Additionally this approachcan also be used to monitor the ligand dependent association of afluorescently labeled coactivator peptide to the nuclear receptor ofinterest to detect ligand binding to the nuclear receptor of interest.

The ability of a compound to bind to a receptor, or heterodimer complexwith RXR, can also be measured in a homogeneous assay format byassessing the degree to which the compound can compete off aradiolabelled ligand with known affinity for the receptor using ascintillation proximity assay (SPA). In this approach, the radioactivityemitted by a radiolabelled compound generates an optical signal when itis brought into close proximity to a scintillant such as a Ysi-coppercontaining bead, to which the nuclear receptor is bound. If theradiolabelled compound is displaced from the nuclear receptor the amountof light emitted from the nuclear receptor bound scintillant decreases,and this can be readily detected using standard microplate liquidscintillation plate readers such as, for example, a Wallac MicroBetareader.

The heterodimerization of FXR with RXRα can also be measured byfluorescence resonance energy transfer (FRET), or time resolved FRET, tomonitor the ability of the compounds provided herein to bind to FXR orother nuclear receptors. Both approaches rely upon the fact that energytransfer from a donor molecule to an acceptor molecule only occurs whendonor and acceptor are in close proximity. Typically the purified LBD ofthe nuclear receptor of interest is labeled with biotin then mixed withstoichiometric amounts of europium labeled streptavidin (Wallac Inc.),and the purified LBD of RXRα is labeled with a suitable fluorophore suchas CY5™. Equimolar amounts of each modified LBD are mixed together andallowed to equilibrate for at least 1 hour prior to addition to eithervariable or constant concentrations of the sample for which the affinityis to be determined. After equilibration, the time-resolved fluorescentsignal is quantitated using a fluorescent plate reader. The affinity ofthe compound can then be estimated from a plot of fluorescence versusconcentration of compound added.

This approach can also be exploited to measure the ligand dependentinteraction of a co-activator peptide with a nuclear receptor in orderto characterize the agonist or antagonist activity of the compoundsdisclosed herein. Typically the assay in this case involves the use arecombinant Glutathione-S-transferase (GST)-nuclear receptor ligandbinding domain (LBD) fusion protein and a synthetic biotinylated peptidesequenced derived from the receptor interacting domain of a co-activatorpeptide such as the steroid receptor coactivator 1 (SRC-1). TypicallyGST-LBD is labeled with a europium chelate (donor) via a europium-taggedanti-GST antibody, and the coactivator peptide is labeled withallophycocyanin via a streptavidin-biotin linkage.

In the presence of an agonist for the nuclear receptor, the peptide isrecruited to the GST-LBD bringing europium and allophycocyanin intoclose proximity to enable energy transfer from the europium chelate tothe allophycocyanin. Upon excitation of the complex with light at 340 nmexcitation energy absorbed by the europium chelate is transmitted to theallophycocyanin moiety resulting in emission at 665 nm. If the europiumchelate is not brought in to close proximity to the allophycocyaninmoiety there is little or no energy transfer and excitation of theeuropium chelate results in emission at 615 nm. Thus the intensity oflight emitted at 665 nm gives an indication of the strength of theprotein-protein interaction. The activity of a nuclear receptorantagonist can be measured by determining the ability of a compound tocompetitively inhibit (i.e., IC₅₀) the activity of an agonist for thenuclear receptor.

In addition a variety of cell based assay methodologies may besuccessfully used in screening assays to identify and profile thespecificity of compounds of the present invention. These approachesinclude the co-transfection assay, translocation assays, complementationassays and the use of gene activation technologies to over expressendogenous nuclear receptors.

Three basic variants of the co-transfection assay strategy exist,co-transfection assays using full-length nuclear receptor, cotransfection assays using chimeric nuclear receptors comprising theligand binding domain of the nuclear receptor of interest fused to aheterologous DNA binding domain, and assays based around the use of themammalian two hybrid assay system.

The basic co-transfection assay is based on the co-transfection into thecell of an expression plasmid to express the nuclear receptor ofinterest in the cell with a reporter plasmid comprising a reporter genewhose expression is under the control of DNA sequence that is capable ofinteracting with that nuclear receptor. (See for example U.S. Pat. Nos.5,071,773; 5,298,429 and 6,416,957).Treatment of the transfected cellswith an agonist for the nuclear receptor increases the transcriptionalactivity of that receptor which is reflected by an increase inexpression of the reporter gene, which may be measured by a variety ofstandard procedures.

For those receptors that function as heterodimers with RXR, such as FXR,the co-transfection assay typically includes the use of expressionplasmids for both the nuclear receptor of interest and RXR. Typicalco-transfection assays require access to the full length nuclearreceptor and suitable response elements that provide sufficientscreening sensitivity and specificity to the nuclear receptor ofinterest.

Genes encoding the following full-length previously described proteins,which are suitable for use in the co-transfection studies and profilingthe compounds described herein, include rat FXR (SEQ ID NO. 5), humanFXR (SEQ ID NO.7), human RXR α (SEQ ID NO. 9), human RXR β (SEQ ID NO.17), human RXR.γ (SEQ ID NO. 15), human LXR α (SEQ ID NO. 1), human LXRβ (SEQ ID NO. 3),human PPARα (SEQ ID NO. 11) and human PPAR δ (SEQ IDNO. 13).

Reporter plasmids may be constructed using standard molecular biologicaltechniques by placing cDNA encoding for the reporter gene downstreamfrom a suitable minimal promoter. For example luciferase reporterplasmids may be constructed by placing cDNA encoding firefly luciferaseimmediately down stream from the herpes virus thymidine kinase promoter(located at nucleotides residues-105 to +51 of the thymidine kinasenucleotide sequence) which is linked in turn to the various responseelements.

Numerous methods of co-transfecting the expression and reporter plasmidsare known to those of skill in the art and may be used for theco-transfection assay to introduce the plasmids into a suitable celltype. Typically such a cell will not endogenously express nuclearreceptors that interact with the response elements used in the reporterplasmid.

Numerous reporter gene systems are known in the art and include, forexample, alkaline phosphatase Berger, J., et al. (1988) Gene 66 1-10;Kain, S. R. (1997) Methods. Mol. Biol. 63 49-60), β-galactosidase (See,U.S. Pat. No. 5,070,012, issued Dec., 3, 1991 to Nolan et al., andBronstein, I., et al., (1989) J. Chemilum. Biolum. 4 99-111),chloramphenicol acetyltransferase (See Gorman et al., Mol Cell Biol.(1982) 2 1044-51), β-glucuronidase, peroxidase, β-lactamase (U.S. Pat.Nos. 5,741,657 and 5,955,604), catalytic antibodies, luciferases (U.S.Pat. Nos. 5,221,623; 5,683,888; 5,674,713; 5,650,289; 5,843,746) andnaturally fluorescent proteins (Tsien, R. Y. (1998) Annu. Rev. Biochem.67 509-44).

The use of chimeras comprising the ligand binding domain (LBD) of thenuclear receptor of interest to a heterologous DNA binding domain (DBD)expands the versatility of cell based assays by directing activation ofthe nuclear receptor in question to defined DNA binding elementsrecognized by defined DNA binding domain (see WO95/18380). This assayexpands the utility of cell based co-transfection assays in cases wherethe biological response or screening window using the native DNA bindingdomain is not satisfactory.

In general the methodology is similar to that used with the basicco-transfection assay, except that a chimeric construct is used in placeof the full length nuclear receptor. As with the full length nuclearreceptor, treatment of the transfected cells with an agonist for thenuclear receptor LBD increases the transcriptional activity of theheterologous DNA binding domain which is reflected by an increase inexpression of the reporter gene as described above. Typically for suchchimeric constructs, the DNA binding domains from defined nuclearreceptors, or from yeast or bacterially derived transcriptional.regulators such as members of the GAL 4 and Lex A/Umud super familiesare used.

A third cell based assay of utility for screening compounds of thepresent invention is a mammalian two-hybrid assay that measures theability of the nuclear hormone receptor to interact with a cofactor inthe presence of a ligand. (See for example, U.S. Pat. Nos. 5,667,973,5,283,173 and 5,468,614). The basic approach is to create three plasmidconstructs that enable the interaction of the nuclear receptor with theinteracting protein to be coupled to a transcriptional readout within aliving cell. The first construct is an expression plasmid for expressinga fusion protein comprising the interacting protein, or a portion ofthat protein containing the interacting domain, fused to a GAL4 DNAbinding domain. The second expression plasmid comprises DNA encoding thenuclear receptor of interest fused to a strong transcription activationdomain such as VP16, and the third construct comprises the reporterplasmid comprising a reporter gene with a minimal promoter and GAL4upstream activating sequences.

Once all three plasmids are introduced into a cell, the GAL4 DNA bindingdomain encoded in the first construct allows for specific binding of thefusion protein to GAL4 sites upstream of a minimal promoter. Howeverbecause the GAL4 DNA binding domain typically has no strongtranscriptional activation properties in isolation, expression of thereporter gene occurs only at a low level. In the presence of a ligand,the nuclear receptor-VP16 fusion protein can bind to theGAL4-interacting protein fusion protein bringing the strongtranscriptional activator VP16 in close proximity to the GAL4 bindingsites and minimal promoter region of the reporter gene. This interactionsignificantly enhances the transcription of the reporter gene, which canbe measured for various reporter genes as described above. Transcriptionof the reporter gene is thus driven by the interaction of theinteracting protein and nuclear receptor of interest in a liganddependent fashion.

Any compound which is a candidate for activation of FXR may be tested bythese methods. Generally, compounds are tested at several differentconcentrations to optimize the chances that activation of the receptorwill be detected and recognized if present. Typically assays areperformed in triplicate and vary within experimental error by less than15%. Each experiment is typically repeated three or more times withsimilar results.

Activity of the reporter gene can be conveniently normalized to theinternal control and the data plotted as fold activation relative tountreated cells. A positive control compound (agonist) may be includedalong with DMSO as high and low controls for normalization of the assaydata. Similarly, antagonist activity can be measured by determining theability of a compound to competitively inhibit the activity of anagonist.

Additionally the compounds and compositions can be evaluated for theirability to increase or decrease the expression of genes known to bemodulated by FXR and other nuclear receptors in vivo, usingNorthern-blot, RT PCR or oligonucleotide microarray analysis to analyzeRNA levels. Western-blot analysis can be used to measure expression ofproteins encoded by FXR target genes. Genes that are known to beregulated by the FXR include cholesterol 7 a-hydroxylase (CYP7A1), therate limiting enzyme in the conversion of cholesterol to bile acids, thesmall heterodimer partner-1 (SHP-1), the bile salt export pump (BSEP,ABCB11), canalicular bile acid export protein, sodium taurocholatecotransporting polypeptide (NTCP, SLC10A1) and intestinal bile acidbinding protein (I-BABP).

Established animal models exist for a number of diseases of directrelevance to the claimed compounds and these can be used to furtherprofile and characterize the claimed compounds. These model systemsinclude diabetic dislipidemia using Zucker (fa/fa) rats or (db/db) mice,spontaneous hyperlipidemia using apolipoprotein E deficient mice(ApoE^(-l-)), diet-induced hyperlipidemia, using low density lipoproteinreceptor deficient mice (LDR^(-l-)) and atherosclerosis using both theApo E(^(-l-)) and LDL(^(-l-)) mice fed a western diet. (21% fat, 0.05%cholesterol). Additionally FXR or LXR animal models (e.g., knockoutmice) can be used to further evaluate the present compounds andcompositions in vivo (see, for example, Sinal, et al., Cell, 102:731-744 (2000), Peet, et al., Cell, 93:693-704 (1998)).

F. Methods of Use of the Compounds and Compositions

Methods of use of the compounds and compositions provided herein arealso provided. The methods involve both in vitro and in vivo uses of thecompounds and compositions for altering nuclear receptor activity,including FXR, LXR and/or orphan nuclear receptor activity, and fortreatment, prevention, or amelioration of one or more symptoms ofdiseases or disorder that are modulated by nuclear receptor activity,including FXR, LXR and/or orphan nuclear receptor activity, or in whichnuclear receptor activity, including FXR, LXR and/or orphan nuclearreceptor activity, is implicated.

Methods of reducing cholesterol levels and of modulating cholesterolmetabolism are provided. As described above, FXR is implicated inmodulating cholesterol metabolism, catabolism and absorption of dietarycholesterol. See, e.g., International Patent Application Publication No.00/40965.

Method of altering nuclear receptor activity, including FXR, LXR and/ororphan nuclear receptor activity, by contacting the receptor with one ormore compounds or compositions provided herein, are provided.

Methods of treatment, prevention, or amelioration of one or moresymptoms of a disease or disorder which is affected by cholesterol,triglyceride, or bile acid levels are provided.

Methods of treatment, prevention, or amelioration of one or moresymptoms of hypercholesterolemia (see, e.g., International PatentApplication Publication No. WO 00/57915); hyperlipoproteinemia (see,e.g., International Patent Application Publication No. WO 01/60818);hypertriglyceridemia, lipodystrophy, hyperglycemia or diabetes mellitus(see, e.g., International Patent Application Publication No. WO01/82917); dyslipidemia, obesity, atherosclerosis, lipid disorders,cardiovascular disorders, or gallstone disease (see, e.g., InternationalPatent Application Publication No. WO 00/37077); acne vulgaris oracneiform skin conditions (see, e.g., International Patent ApplicationPublication No. WO 00/49992); atherosclerosis, diabetes, Parkinson'sdisease, inflammation, immunological disorders, obesity, cancer orAlzheimer's disease (see, e.g., International Patent ApplicationPublication No. WO 00/17334); conditions characterized by a perturbedepidermal barrier function, hyperlipidemia, cholestasis, peripheralocclusive disease, ischemic stroke, or conditions of disturbeddifferentiation or excess proliferation of the epidermis or mucousmembrane (see, e.g., U.S. Pat. Nos. 6,184,215 and 6,187,814, andInternational Patent Application Publication No. WO 98/32444) areprovided.

Methods of increasing cholesterol efflux from mammalian cells using thecompounds and compositions provided herein are provided (see, e.g.,International Patent Application Publication No. WO 00/78972).

Methods of increasing the expression of ATP-Binding Cassette (ABC1) inmammalian cells using the compounds and compositions provided herein areprovided (see, e.g., International Patent Application Publication No. WO00/78972).

Further provided herein are methods for the treatment, prevention, oramelioration of one or more symptoms of cholestasis, as well as treatingthe complications of cholestasis by administering a compound providedherein.

Cholestasis is typically caused by factors within the liver(intrahepatic) or outside the liver (extrahepatic) and leads to theaccumulation of bile salts, bile pigment bilirubin, and lipids in theblood stream instead of being eliminated normally.

Intrahepatic cholestasis is characterized by widespread blockage ofsmall ducts or by disorders, such as hepatitis, that impair the body'sability to eliminate bile. Intrahepatic cholestasis may also be causedby alcoholic liver disease, primary biliary cirrhosis, cancer that hasspread (metastasized) from another part of the body, primary sclerosingcholangitis, gallstones, biliary colic and acute cholecystitis. It canalso occur as a complication of surgery, serious injury, infection, orintravenous feeding or be drug induced. Cholestasis may also occur as acomplication of pregnancy and often develops during the second and thirdtrimesters.

Extrahepatic cholestasis is most often caused by choledocholithiasis(Bile Duct Stones), benign biliary strictures (non-cancerous narrowingof the common duct), cholangiocarcinoma (ductal carcinoma) andpancreatic carcinoma. Extrahepatic cholestasis can occur as a sideeffect of many medications.

Accordingly, compounds provided herein may be used for the treatment,prevention, or amelioration of one or more symptoms of intrahepatic orextrahepatic cholestasis, including without limitation, biliary artesia,obstetric cholestasis, neonatal cholestasis, drug induced cholestasis,cholestasis arising from Hepatitis C infection, chronic cholestaticliver disease such as primary biliary cirrhosis (PBC) and primarysclerosing cholangitis (PSC).

Methods of treating, preventing, or ameliorating one or more symptoms ofhypocholesterolemia using the compounds and compositions provided hereinare also provided.

G. Combination Therapy

Also contemplated herein is combination therapy using a compoundprovided herein, or a pharmaceutically acceptable derivative thereof, incombination with one or more of the following: antihyperlipidemicagents, plasma HDL-raising agents, antihypercholesterolemic agents,cholesterol biosynthesis inhibitors (such as HMG CoA reductaseinhibitors, such as lovastatin, simvastatin, pravastatin, fluvastatin,atorvastatin and rivastatin), acyl-coenzyme A:cholesterol acytransferase(ACAT) inhibitors, probucol, raloxifene, nicotinic acid, niacinamide,cholesterol absorption inhibitors, bile acid sequestrants (such as anionexchange resins, or quaternary amines (e.g., cholestyramine orcolestipol)), low density lipoprotein receptor inducers, clofibrate,fenofibrate, benzofibrate, cipofibrate, gemfibrizol, vitamin B₆, vitaminB₁₂, anti-oxidant vitamins, β-blockers, anti-diabetes agents,angiotensin II antagonists, angiotensin converting enzyme inhibitors,platelet aggregation inhibitors, fibrinogen receptor antagonists,aspirin or fibric acid derivatives. The compound provided herein, orpharmaceutically acceptable derivative thereof, is administeredsimultaneously with, prior to, or after administration of one or more ofthe above agents. Pharmaceutical compositions containing a compoundprovided herein and one or more of the above agents are also provided.

Combination therapy includes administration of a single pharmaceuticaldosage formulation which contains a FXR selective compound and one ormore additional active agents, as well as administration of the FXRselective compound and each active agent in its own separatepharmaceutical dosage formulation. For example, a FXR agonist orantagonist of the present invention and an HMG-CoA reductase inhibitorcan be administered to the patient together in a single oral dosagecomposition such as a tablet or capsule, or each agent administered inseparate oral dosage formulations. Where separate dosage formulationsare used, the compounds described herein and one or more additionalactive agents can be administered at essentially the same time, i.e.,concurrently, or at separately staggered times, i.e., sequentially;combination therapy is understood to include all these regimens.

The compound is preferably administered with a cholesterol biosynthesisinhibitor, particularly an HMG-CoA reductase inhibitor. The term HMG-CoAreductase inhibitor is intended to include all pharmaceuticallyacceptable salt, ester, free acid and lactone forms of compounds whichhave HMG-CoA reductase inhibitory activity and, therefore, the use ofsuch salts, esters, free acids and lactone forms is included within thescope of this invention. Compounds which have inhibitory activity forHMG-CoA reductase can be readily identified using assays well-known inthe art. For instance, suitable assays are described or disclosed inU.S. Pat. No. 4,231,938 and WO 84/02131. Examples of suitable HMG-CoAreductase inhibitors include, but are not limited to, lovastatin(MEVACOR®; see, U.S. Pat. No. 4,231,938); simvastatin (ZOCOR®; see, U.S.Pat. No. 4,444,784); pravastatin sodium (PRAVACHOL®; see, U.S. Pat. No.4,346,227); fluvastatin sodium (LESCOL®; see, U.S. Pat. No. 5,354,772);atorvastatin calcium (LIPITOR®; see, U.S. Pat. No. 5,273,995) andrivastatin (also known as cerivastatin; see, U.S. Pat. No. 5,177,080).The structural formulas of these and additional HMG-CoA reductaseinhibitors that can be used in the methods of the present invention aredescribed at page 87 of M. Yalpani, “Cholesterol Lowering Drugs,”Chemistry & Industry, pp. 85-89 (5 February 1996). In presentlypreferred embodiments, the HMG-CoA reductase inhibitor is selected fromlovastatin and simvastatin.

Dosage information for HMG-CoA reductase inhibitors is well known in theart, since several HMG-CoA reductase inhibitors are marketed in the U.S.In particular, the daily dosage amounts of the HMG-CoA reductaseinhibitor may be the same or similar to those amounts which are employedfor anti-hypercholesterolemic treatment and which are described in thePhysicians' Desk Reference (PDR). For example, see the 50th Ed. of thePDR, 1996 (Medical Economics Co); in particular, see at page 216 theheading “Hypolipidemics,” sub-heading “HMG-CoA Reductase Inhibitors,”and the reference pages cited therein. Preferably, the oral dosageamount of HMG-CoA reductase inhibitor is from about 1 to 200 mg/day and,more preferably, from about 5 to 160 mg/day. However, dosage amountswill vary depending on the potency of the specific HMG-CoA reductaseinhibitor used as well as other factors as noted above. An HMG-CoAreductase inhibitor which has sufficiently greater potency may be givenin sub-milligram daily dosages.

As examples, the daily dosage amount for simvastatin may be selectedfrom 5 mg, 10 mg, 20 mg, 40 mg, 80 mg and 160 mg for lovastatin, 10 mg,20 mg, 40 mg and 80 mg; for fluvastatin sodium, 20 mg, 40 mg and 80 mg;and for pravastatin sodium, 10 mg, 20 mg, and 40 mg. The daily dosageamount for atorvastatin calcium may be in the range of from 1 mg to 160mg and, more particularly, from 5 mg to 80 mg. Oral administration maybe in a single or divided doses of two, three, or four times daily,although a single daily dose of the HMG-CoA reductase inhibitor ispreferred.

The compounds of the present invention can be utilized in methods fordecreasing hyperglycemia and insulin resistance or for methods oftreating type II diabetes. The compounds can be identified, formulated,and administered as described above.

Diabetes mellitus, commonly called diabetes, refers to a disease processderived from multiple causative factors and characterized by elevatedlevels of plasma glucose, referred to as hyperglycemia. See, e.g.,LeRoith, D. et al., (eds.), DIABETES MELLITUS (Lippincott-RavenPublishers, Philadelphia, Pa. U.S.A. 1996). According to the AmericanDiabetes Association, diabetes mellitus is estimated to affectapproximately 6% of the world population. Uncontrolled hyperglycemia isassociated with increased and premature mortality due to an increasedrisk for macrovascular and macrovascular diseases, includingnephropathy, neuropathy, retinopathy, hypertension, cerebrovasculardisease and coronary heart disease. Therefore, control of glucosehomeostasis is a critically important approach for the treatment ofdiabetes.

There are two major forms of diabetes: type 1 diabetes (formerlyreferred to as insulin-dependent diabetes or IDEM); and type 2 diabetes(formerly referred to as noninsulin dependent diabetes or NIDDM).

Type 2 diabetes is a disease characterized by insulin resistanceaccompanied by relative, rather than absolute, insulin deficiency. Type2 diabetes can range from predominant insulin resistance with relativeinsulin deficiency to predominant insulin deficiency with some insulinresistance. Insulin resistance is the diminished ability of insulin toexert its biological action across a broad range of concentrations. Ininsulin resistant individuals, the body secretes abnormally high amountsof insulin to compensate for this defect. When inadequate amounts ofinsulin are present to compensate for insulin resistance and adequatecontrol of glucose, a state of impaired glucose tolerance develops. In asignificant number of individuals, insulin secretion declines furtherand the plasma glucose level rises, resulting in the clinical state ofdiabetes. Type 2 diabetes can be due to a profound resistance to insulinstimulating regulatory effects on glucose and lipid metabolism in themain insulin-sensitive tissues: muscle, liver and adipose tissue. Thisresistance to insulin responsiveness results in insufficient insulinactivation of glucose uptake, oxidation and storage in muscle andinadequate insulin repression of lipolysis in adipose tissue and ofglucose production and secretion in liver. In Type 2 diabetes, freefatty acid levels are often elevated in obese and some non-obesepatients and lipid oxidation is increased.

Premature development of atherosclerosis and increased rate ofcardiovascular and peripheral vascular diseases are characteristicfeatures of patients with diabetes. Hyperlipidemia is an importantprecipitating factor for these diseases. Hyperlipidemia is a conditiongenerally characterized by an abnormal increase in serum lipids in thebloodstream and is an important risk factor in developingatherosclerosis and heart disease. For a review of disorders of lipidmetabolism, see, e.g., Wilson, J. et al., (ed.), Disorders of LipidMetabolism, Chapter 23, Textbook of Endocrinology, 9th Edition, (W.B.Sanders Company, Philadelphia, Pa. U.S.A. 1998). Hyperlipidemia isusually classified as primary or secondary hyperlipidemia. Primaryhyperlipidemia is generally caused by genetic defects, while secondaryhyperlipidemia is generally caused by other factors, such as variousdisease states, drugs, and dietary factors. Alternatively,hyperlipidemia can result from both a combination of primary andsecondary causes of hyperlipidemia. Elevated cholesterol levels areassociated with a number of disease states, including coronary arterydisease, angina pectoris, carotid artery disease, strokes, cerebralarteriosclerosis, and xanthoma.

Dyslipidemia, or abnormal levels of lipoproteins in blood plasma, is afrequent occurrence among diabetics, and has been shown to be one of themain contributors to the increased incidence of coronary events anddeaths among diabetic subjects (see, e.g., Joslin, E. Ann. Chim. Med.(1927) 5: 1061-1079). Epidemiological studies since then have confirmedthe association and have shown a several-fold increase in coronarydeaths among diabetic subjects when compared with nondiabetic subjects(see, e.g., Garcia, M. J. et al., Diabetes (1974) 23: 105-11 (1974); andLaakso, M. and Lehto, S., Diabetes Reviews (1997) 5(4): 294-315).Several lipoprotein abnormalities have been described among diabeticsubjects (Howard B., et al., Arteriosclerosis (1978) 30: 153-162).

The term “insulin resistance” can be defined generally as a disorder ofglucose metabolism. More specifically, insulin resistance can be definedas the diminished ability of insulin to exert its biological actionacross a broad range of concentrations producing less than the expectedbiologic effect. (see, e.g., Reaven, G. M., J. Basic & Clin. Phys. &Pharm. (1998) 9: 387-406 and Flier, J. Ann Rev. Med. (1983) 34:145-60).Insulin resistant persons have a diminished ability to properlymetabolize glucose and respond poorly, if at all, to insulin therapy.Manifestations of insulin resistance include insufficient insulinactivation of glucose uptake, oxidation and storage in muscle andinadequate insulin repression of lipolysis in adipose tissue and ofglucose production and secretion in liver. Insulin resistance can causeor contribute to polycystic ovarian syndrome, Impaired Glucose Tolerance(IGT), gestational diabetes, hypertension, obesity, atherosclerosis anda variety of other disorders. Eventually, the insulin resistantindividuals can progress to a point where a diabetic state is reached.The association of insulin resistance with glucose intolerance, anincrease in plasma triglyceride and a decrease in high-densitylipoprotein cholesterol concentrations, high blood pressure,hyperuricemia, smaller denser low-density lipoprotein particles, andhigher circulating levels of plasminogen activator inhibitor-1), hasbeen referred to as “Syndrome X” (see, e.g., Reaven, G. M., Physiol.Rev. (1995) 75: 473-486).

The term “diabetes mellitus” or “diabetes” means a disease or conditionthat is generally characterized by metabolic defects in production andutilization of glucose which result in the failure to maintainappropriate blood sugar levels in the body. The result of these defectsis elevated blood glucose, referred to as “hyperglycemia.” Type 2diabetes often occurs in the face of normal, or even elevated, levels ofinsulin and can result from the inability of tissues to respondappropriately to insulin. Most type 2 diabetic patients are insulinresistant and have a relative deficiency of insulin, in that insulinsecretion can not compensate for the resistance of peripheral tissues torespond to insulin. In addition, many type 2 diabetics are obese. Othertypes of disorders of glucose homeostasis include Impaired GlucoseTolerance, which is a metabolic stage intermediate between normalglucose homeostasis and diabetes, and Gestational Diabetes Mellitus,which is glucose intolerance in pregnancy in women with no previoushistory of type 1 or type 2 diabetes.

The term “complication” of diabetes includes, but is not limited to,microvascular complications and macrovascular complications.Microvascular complications are those complications which generallyresult in small blood vessel damage. These complications include, e.g.,retinopathy (the impairment or loss of vision due to blood vessel damagein the eyes); neuropathy (nerve damage and foot problems due to bloodvessel damage to the nervous system); and nephropathy (kidney diseasedue to blood vessel damage in the kidneys). macrovascular complicationsare those complications which generally result from large blood vesseldamage. These complications include, e.g., cardiovascular disease andperipheral vascular disease. Cardiovascular disease refers to diseasesof blood vessels of the heart. See. e.g., Kaplan, R. M., et al.,“Cardiovascular diseases” in HEALTH AND HUMAN BEHAVIOR, pp. 206-242(McGraw-Hill, New York 1993). Cardiovascular disease is generally one ofseveral forms, including, e.g., hypertension (also referred to as highblood pressure), coronary heart disease, stroke, and rheumatic heartdisease. Peripheral vascular disease refers to diseases of any of theblood vessels outside of the heart. It is often a narrowing of the bloodvessels that carry blood to leg and arm muscles.

The term “hyperlipidemia” refers to the presence of an abnormallyelevated level of lipids in the blood. Hyperlipidemia can appear in atleast three forms: (1) hypercholesterolemia, i.e., an elevatedcholesterol level; (2) hypertriglyceridemia, i.e., an elevatedtriglyceride level; and (3) combined hyperlipidemia, i.e., a combinationof hypercholesterolemia and hypertriglyceridemia.

The term “cholesterol” refers to a steroid alcohol that is an essentialcomponent of cell membranes and myelin sheaths and, as used herein,incorporates its common usage. Cholesterol also serves as a precursorfor steroid hormones and bile acids.

The term “triglyceride(s)” (“TGs”), as used herein, incorporates itscommon usage. TGs consist of three fatty acid molecules esterified to aglycerol molecule and serve to store fatty acids which are used bymuscle cells for energy production or are taken up and stored in adiposetissue.

The term “dyslipidemia” refers to abnormal levels of lipoproteins inblood plasma including both depressed and/or elevated levels oflipoproteins (e.g., elevated levels of LDL, VLDL and depressed levels ofHDL).

Exemplary Primary Hypedipidemia include, but are not limited to, thefollowing: (1) Familial Hyperchylomicronemia, a rare genetic disorderwhich causes a deficiency in an enzyme, LP lipase, that breaks down fatmolecules. The LP lipase deficiency can cause the accumulation of largequantities of fat or lipoproteins in the blood;

(2) Familial Hypercholesterolemia, a relatively common genetic disordercaused where the underlying defect is a series of mutations in the LDLreceptor gene that result in malfunctioning LDL receptors and/or absenceof the LDL receptors. This brings about ineffective clearance of LDL bythe LDL receptors resulting in elevated LDL and total cholesterol levelsin the plasma;

(3) Familial Combined Hypedipidemia, also known as multiplelipoprotein-type hyperlipidemia; an inherited disorder where patientsand their affected first-degree relatives can at various times manifesthigh cholesterol and high triglycerides. Levels of HDL cholesterol areoften moderately decreased;

(4) Familial Defective Apolipoprotein B-100 is a relatively commonautosomal dominant genetic abnormality. The defect is caused by a singlenucleotide mutation that produces a substitution of glutamine forarginine which can cause reduced affinity of LDL particles for the LDLreceptor. Consequently, this can cause high plasma LDL and totalcholesterol levels;

(5) Familial Dysbetaliproteinemia, also referred to as Type IIIHyperlipoproteinemia, is an uncommon inherited disorder resulting inmoderate to severe elevations of serum TG and cholesterol levels withabnormal apolipoprotein E function. HDL levels are usually normal; and

(6) Familial Hypertriglyceridemia, is a common inherited disorder inwhich the concentration of plasma VLDL is elevated. This can cause mildto moderately elevated triglyceride levels (and usually not cholesterollevels) and can often be associated with low plasma HDL levels.

Risk factors in exemplary Secondary Hyperlipidemia include, but are notlimited to, the following: (1) disease risk factors, such as a historyof type 1 diabetes, type 2 diabetes, Cushing's syndrome, hypothyroidismand certain types of renal failure; (2) drug risk factors, whichinclude, birth control pills; hormones, such as estrogen, andcorticosteroids; certain diuretics; and various .beta. blockers; (3)dietary risk factors include dietary fat intake per total caloriesgreater than 40%; saturated fat intake per total calories greater than10%; cholesterol intake greater than 300 mg per day; habitual andexcessive alcohol use; and obesity; and (4) non-genetic dyslipidemias.

The methods of the present invention can be used effectively incombination with one or more additional active diabetes agents dependingon the desired target therapy (see, e.g., Turner, N. et al. Prog. DrugRes. (1998) 51: 33-94; Haffner, S. Diabetes Care (1998) 21: 160-178; andDeFronzo, R. et al. (eds.), Diabetes Reviews (1997) Vol. 5 No. 4). Anumber of studies have investigated the benefits of combinationtherapies with oral agents (see, e.g., Mahler, R., J. Clin. Endocrinol.Metab. (1999) 84: 1165-71; United Kingdom Prospective Diabetes StudyGroup: UKPDS 28, Diabetes Care (1998) 21: 87-92; Bardin, C. W.,(ed.),CURRENT THERAPY IN ENDOCRINOLOGY AND METABOLISM, 6th Edition (Mosby—YearBook, Inc., St. Louis, Mo. 1997); Chiasson, J. et al., Ann. Intern. Med.(1994) 121: 928-935; Coniff, R. et al., Clin. Ther. (1997) 19:16-26;Coniff, R. et al., Am. J. Med. (1995) 98: 443-451; and Iwamoto, Y. etal, Diabet. Med. (1996) 13 365-370; Kwiterovich, P. Am. J. Cardiol(1998) 82(12A): 3U-17U). These studies indicate that diabetes andhyperlipidemia modulation can be further improved by the addition of asecond agent to the therapeutic regimen.

An example of combination therapy that modulates (prevents the onset ofthe symptoms or complications associated) atherosclerosis, isadministered with one or more of the following active agents: anantihyperlipidemic agent; a plasma HDL-raising agent; anantihypercholesterolemic agent, such as a cholesterol biosynthesisinhibitor, e.g., an hydroxymethylglutaryl (HMG) CoA reductase inhibitor(also referred to as statins, such as lovastatin, simvastatin,pravastatin, fluvastatin, and atorvastatin), an HMG-CoA synthaseinhibitor, a squalene epoxidase inhibitor, or a squalene synthetaseinhibitor (also known as squalene synthase inhibitor); an acyl-coenzymeA cholesterol acyltransferase (ACAT) inhibitor, such as melinamide;probucol; nicotinic acid and the salts thereof and niacinamide; acholesterol absorption inhibitor, such as β-sitosterol; a bile acidsequestrant anion exchange resin, such as cholestyramine, colestipol ordialkylaminoalkyl derivatives of a cross-linked dextran; an LDL (lowdensity lipoprotein) receptor inducer; fibrates, such as clofibrate,bezafibrate, fenofibrate, and gemfibrizol; vitamin B₆ (also known aspyridoxine) and the pharmaceutically acceptable salts thereof, such asthe HCl salt; vitamin B₁₂ (also known as cyanocobalamin); vitamin B₃(also known as nicotinic acid and niacinamide, supra); anti-oxidantvitamins, such as vitamin C and E and beta carotene; a beta-blocker; anangiotensin II antagonist; an angiotensin converting enzyme inhibitor;and a platelet aggregation inhibitor, such as fibrinogen receptorantagonists (i.e., glycoprotein IIb/IIIa fibrinogen receptorantagonists) and aspirin.

Still another example of combination therapy can be seen in modulatingdiabetes (or treating diabetes and its related symptoms, complications,and disorders) with, for example, sulfonylureas (such as chlorpropamide,tolbutamide, acetohexamide, tolazamide, glyburide, gliclazide, glynase,glimepiride, and glipizide), biguanides (such as metformin),thiazolidinediones (such as ciglitazone, pioglitazone, troglitazone, androsiglitazone); and related insulin sensitizers, such as selective andnon-selective activators of PPARα, PPARβ and PPARγ;dehydroepiandrosterone (also referred to as DHEA or its conjugatedsulphate ester, DHEA-SO₄); antiglucocorticoids; TNFαinhibitors;α-glucosidase inhibitors (such as acarbose, miglitol, and voglibose),pramlintide (a synthetic analog of the human hormone amylin), otherinsulin secretogogues (such as repaglinide, gliquidone, andnateglinide), insulin, as well as the active agents discussed above fortreating atherosclerosis.

Further provided by this invention are methods for treating obesity, aswell as treating the complications of obesity, by administering acompound of the present invention. The antagonists can be identified,formulated, and administered similarly to the information describedabove. A FXR selective antagonist includes a partial agonist/antagonistor antagonist that exhibits about a two to about a ten-fold preferencefor FXR compared to another nuclear receptor such as, for example LXR αor β with respect to potency (IC₅₀, the concentration of compound thatachieves 50% of the maximum reduction in the transcription activityachieved by the compound of interest observed in the presence of asub-maximal concentration of FXR agonist) and/or efficacy (the maximumpercent inhibition of transcription observed with the compound inquestion).

The terms “obese” and “obesity” refers to, according to the World HealthOrganization, a Body Mass Index (BMI) greater than 27.8 kg/m² for menand 27.3 kg/m² for women (BMI equals weight (kg)/height (m²). Obesity islinked to a variety of medical conditions including diabetes andhyperlipidemia. Obesity is also a known risk factor for the developmentof type 2 diabetes (See, e.g., Barrett-Conner, E., Epidemol. Rev. (1989)11: 172-181; and Knowler, et al., Am. J Clin. Nutr. (1991)53:1543-1551).

Another example of combination therapy can be seen in treating obesityor obesity-related disorders, wherein the methods can be effectivelyused in combination with, for example, phenylpropanolamine, phentermine,diethylpropion, mazindol; fenfluramine, dexfenfluramine, phentiramine,β₃ adrenoceptor agonist agents; sibutramine, gastrointestinal lipaseinhibitors (such as orlistat), and leptins. Other agents used intreating obesity or obesity-related disorders include neuropeptide Y,enterostatin, cholecytokinin, bombesin, amylin, histamine H₃ receptors,dopamine D₂ receptors, melanocyte stimulating hormone, corticotrophinreleasing factor, galanin and gamma amino butyric acid (GABA).

Another example of a combination therapy can be seen in treatingcholestasis, where the compounds of the invention can be combined withActigall (Ursodeoxycholic acid—UDCA), corticosteroids, anti-infectiveagents (Rifampin, Rifadin, Rimactane), anti-viral agents, Vitamin D,Vitamin A, phenobarbital, cholestyramine, UV light, antihistamines, oralopiate receptor antagonists and biphosphates, for the treatment,prevention, or amelioration of one or more symptoms of intrahepatic orextrahepatic cholestasis. Dosage information for these agents is wellknown in the art.

The following examples are included for illustrative purposes only andare not intended to limit the scope of the subject matter claimedherein.

EXAMPLE 1 A. Preparation of3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-thioxothiazolidin-4-one

To a 100 mL flask was added anhydrous anisole (14 mL),2-(methylthio)benzothiazole (10.0 g, 55.2 mmol) and methylp-toluenesulfonate (12.5 mL, 82.7 mmol). After heating the mixture at120° C. for 30 min, a crystalline solid precipitated. Anisole (14 mL)was added and the mixture was further heated at 120° C. for 4 h.

After cooling to room temperature, the mixture was then transferred to a1000 mL flask and diluted with anhydrous MeCN (200 mL). To thewell-stirred mixture was added N-benzyl rhodanine (12.3 g, 55.1 mmol)and then dropwise TEA (12.5 mL, 90 mmol). The resulting yellow slurrywas diluted with MeCN (200 mL) and stirred 2 h. The yellow precipitateswere filtered under reduced pressure, washed first with MeCN (50 mL) andthen MeOH (150 mL) to give the crude product.

To a three-neck 1 L flask fitted with a reflux condenser was added thecrude product, acetone (100 mL) and MeOH (200 mL). The mixture wasstirred under reflux for 15 min, cooled to room temperature, filteredunder reduced pressure, washed with MeOH (100 mL) and dried under vacuumfor 24 h to yield the title product (17.4 g, 85%) as a yellow solid,which was used without further purification. ¹H-NMR (CDCl₃): δ 7.61 (1H,dd), 7.55 (2H, m), 7.44 (1H, m), 7.25-7.34 (4H, m), 7.21 (1H, d), 5.37(2H, s), 3.91 (3H, s); MS(ESI): 371 (MH⁺).

B. Preparation of3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio4-oxo-2-thiazoliump-Toluenesulfonate

To a 200 mL flask was added3-benzyl-5-(3-methylbenzothiazolin-2-ylidene)-2-thioxothiazolidin-4-one(5.00 g, 13.5 mmol), methyl p-toluenesulfonate (7.34 mL, 48.6 mmol) andanhydrous DMF(40 mL). After heating at 120° C. for 3 h, the mixture wasallowed to cool to 60° C., transferred to a 1 L flask and diluted withacetone (400 mL). After cooling to room temperature, the precipitate wasfiltered under reduced pressure, washed first with acetone (50 mL) andthen Et₂O (100 mL), and dried under vacuum for 12 h to give the titleproduct (6.25 g, 83%) as a yellow crystalline solid, which was usedwithout further purification. ¹H-NMR (CDCl₃): δ 7.83 (1H, d), 7.75 (2H,m), 7.59-7.66 (2H, m), 7.50 (1H, m), 7.37-7.43 (5H, m), 7.06 (2H, d),5.31 2H, s), 4.52 (3H, s), 3.22 (3H, s), 2.28 (3H, s).

C. Preparation of3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-phenylimino-thiazolidine-4-one

To an 8 mL vial was added3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate (100 mg, 0.18 mmol), aniline (16 μL, 0.18 mmol) andanhydrous MeCN (1 mL). After warming the mixture to 50° C., TEA (0.10mL, 0.56 mmol) was added and continued heating the mixture at 50° C. for12 h. After cooling to room temperature, the resulting precipitates werefiltered under reduced pressure, washed with MeCN (2 mL) and dried undervacuum to yield the title product (22.3 mg, 29%) as a yellow solid.¹H-NMR (CDCl₃): δ 7.59 (2H, m), 7.48 (1H, dd), 7.26-7.39 (6H, m),7.10-7.18 (2H, m) 7.01 (3H, m), 5.16 (2H, s), 3.71 (3H, s); MS(ESI): 430(MH⁺).

EXAMPLE 2 Preparation of3-Benzyl-2-(4-methoxyphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4-anisidine. ¹H-NMR (CDCl₃): δ 7.58(2H, d), 7.48 (1H, d), 7.26-7.35 (4H, m), 7.15 (1H, t), 7.01 (1H, d),6.96 (2H, d), 6.90 (2H, d), 5.16 (2H, s), 3.82 (3H, s), 3.73 (3H, s);MS(ESI): 460 (MH⁺).

EXAMPLE 3 Preparation of3-Benzyl-2-(4-dimethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with N,N-dimethyl-1,4-phenylendiamine.¹H-NMR (CDCl₃): δ 7.59 (2H, d), 7.47 (1H, d), 7.24-7.35 (4H, m), 7.14(1H, t), 6.99 (1H, d), 6.95 (2H, dd), 6.76 (2H, dd), 5.15 (2H, s), 3.73(3H, s), 2.95 (6H, s); MS(ESI): 473 (MH⁺).

EXAMPLE 4 Preparation of2-(4-Aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 1,4-phenylenediamine. ¹H-NMR(CDCl₃): δ 7.58 (2H, m), 7.47 (1H, dd), 7.27-7.34 (4H, m), 7.14 (1H, m),6.99 (1H, d), 6.85 (2H, dd), 6.70 (2H, dd), 5.14 (2H, s), 3.72 (3H, s),3.60 (2H, br); MS(ESI): 445 (MH⁺).

EXAMPLE 5 Preparation of3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin6-ylimino)-thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 6-aminoquinoline. ¹H-NMR (CDCl₃): δ8.84 (1H, dd), 8.09 (2H, d), 7.62 (2H, m), 7.50 (1H, d), 7.43 (1H, dd),7.27-7.40 (6H, m), 7.16 (1H, m), 7.01 (1H, d), 5.20 (2H, s), 3.69 (3H,s); MS(ESI): 481 (MH⁺).

EXAMPLE 6 Preparation of2-(2-Aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 1,2-phenylenediamine. ¹H-NMR(CDCl₃): δ 7.48-7.56 (3H, m), 7.30-7.36 (3H, m), 7.26-29 (1H, m), 7.17(1H, t), 7.03 (1H, d), 6.91-6.99 (2H, m), 6.69-6.77 (2H, m), 5.19 (2H,s), 3.75 (3H, s), 3.49 (2H, s); MS(ESI): 445 (MH⁺).

EXAMPLE 7 Preparation of3-Benzyl-2-(4-benzyloxyphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4-benzyloxyaniline. ¹H-NMR (CDCl₃):δ 7.58 (2H, d), 7.43-7.50 (3H, m), 7.40 (2H, t), 7.26-7.36 (5H, m), 7.15(1H, t), 6.93-7.03 (5H, m), 5.14 (2H, s), 5.07 (2H, s), 3.73 (3H, s);MS(ESI): 536 (MH⁺).

EXAMPLE 8 Preparation of3-Benzyl-2-(2-hydroxy-1-naphthylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 1-amino-2-naphthol hydrochloride.¹H-NMR (CDCl₃): δ 7.79 (1H, d), 7.56-7.64 (3H, m), 7.51 (2H, t),7.28-7.44 (6H, m), 7.21 (1H, d), 7.18 (1H, t), 6.99 (1H, d), 5.34 (2H,s), 5.00 (1H, s), 3.57 (3H, s); MS(ESI): 496 (MH⁺).

EXAMPLE 9 Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 3-aminobenzonitrile. ¹H-NMR(DMSO-d₆): δ 7.72 (1H, d), 7.54 (2H, d), 7.23-7.41 (9H, m), 7.16-7.22(1H, m), 5.02 (2H, s), 3.74 (3H, s); MS(ESI): 455 (MH⁺).

EXAMPLE 10 Preparation of3-Benzyl-2-(4-hydroxy-5-isopropyl-2-methylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4-aminothymol hydrochloride. ¹H-NMR(CDCl₃): δ 7.55-7.60 (2H, m), 7.48 (1H, d), 7.26-7.34 (4H, m), 7.14 (1H,m), 6.99 (1H, d), 6.76 (1H, s), 6.62 (1H, s), 5.17 (2H, s), 4.49 (1H,s), 3.71 (3H, s), 3.17 (1H, m), 1.96 (3H, s), 1.24 (6H, d); MS(ESI): 502(MH⁺).

EXAMPLE 11 Preparation of3-Benzyl-2-(2-ethylamino-5-nitrophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with N¹-ethyl-4-nitrobenzene-1,2-diamine.¹H-NMR (CDCl₃): δ 7.98 (1H, dd), 7.93 (1H, d), 7.55 (1H, d), 7.44 (2H,d), 7.19-7.42 (6H, m), 7.11 (1H, d), 6.46 (1H, d), 5.20 (2H, s), 4.55(1H, br), 3.83 (3H, s), 3.07 (2H, m), 1.05 (3H, t); MS(ESI): 518 (MH⁺).

EXAMPLE 12 Preparation of3-Benzyl-543-methyl-3H-benzothiazol-2-ylidene)-2-[3-(trifluoromethyl)-phenylimino]thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 3-(trifluoromethyl)aniline. ¹H-NMR(CDCl₃): δ 7.57 (2H, m), 7.50 (1H, d), 7.46 (1H, t), 7.24-7.42 (6H, m),7.15-7.21 (2H, m), 7.03 (1H, d), 5.15 (2H, s), 3.73 (3H, s); MS(ESI):498 (MH⁺).

EXAMPLE 13 Preparation of2-(3-Acetylphenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 3′-aminoacetophenone. ¹H-NMR(CDCl₃): δ 7.72 (1H, m), 7.56-7.60 (3H, m), 7.50 (1H, dd), 7.45 (1H, t),7.27-7.37 (4H, m), 7.21 (1H, ddd), 7.17 (1H, m), 7.02 (1H, d), 5.16 (2H,s), 3.72 (3H, s), 2.61 (3H, s); MS(ESI): 472 (MH⁺).

EXAMPLE 14 Preparation of3-Benzyl-2-(3chlorophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 3-chloroaniline. ¹H-NMR (CDCl₃): δ7.54-7.58 (2H, m), 7.49 (1H, dd), 7.26-7.36 (5H, m), 7.17 (1H, m), 7.09(1H, ddd), 7.03 (1H, d), 7.01 (1H, t), 6.89 (1H, ddd), 5.13 (2H, s),3.74 (3H, s); MS(ESI): 464 (MH⁺).

EXAMPLE 15 Preparation of3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-propyl-phenylimino)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 2-propylaniline. ¹H-NMR (CDCl₃): δ7.49 (1H, d), 7.27-7.37 (4H, m), 7.12-7.23 (3H, m), 7.06 (1H, m), 7.00(1H, d), 6.92 (1H, d), 5.17 (2H, s), 3.71 (3H, s), 2.37 (2H, t), 1.42(2H, s), 0.79 (3H, t); MS(ESI): 472 (MH⁺).

EXAMPLE 16 Preparation of3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-5-ylimino)-thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 5-aminoquinoline. ¹H-NMR (CDCl₃): δ8.86 (1H, d), 8.02 (1H, d), 7.81 (1H, d), 7.68 (1H, t), 7.42-7.50 (3H,m), 7.25-7.35 (5H, m), 7.20 (1H, d), 7.12 (1H, t), 7.07 (1H, d), 5.19(2H, s), 3.67 (3H, s); MS(ESI): 481 (MH⁺).

EXAMPLE 17 Preparation of3-Benzyl-2-(2-ethoxyphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with o-phenetidine. ¹H-NMR (CDCl₃): δ7.66 (2H, m), 7.46 (2H, d), 7.24-7.34 (3H, m), 7.07-7.16 (2H, m),6.94-7.00 (4H, m), 5.19 (2H, s), 4.01 (2H, q), 3.69 (3H, s), 1.36 (3H,t); MS(ESI): 474 (MH⁺).

EXAMPLE 18 Preparation ofN-{3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}acetamide

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 3′-aminoacetanilide. ¹H-NMR (CDCl₃):δ 7.57 (2H, d), 7.48 (1H, d), 7.27-7.39 (6H, m), 7.15 (2H, m), 7.06 (1H,br s), 7.01 (1H, d), 6.76 (1H, d), 5.14 (2H, s), 3.72 (3H, s), 2.18 (3H,s); MS(ESI): 487 (MH⁺).

EXAMPLE 19 Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzamide

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 3-aminobenzamide. ¹H-NMR (DMSO-d₆):δ 7.98 (1H, br s), 7.74 (1H, d), 7.62 (1H, d), 7.34-7.48 (9H, m), 7.30(1H, m), 7.21 (1H, m), 7.12 (1H, d), 5.06 (2H, s), 3.75 (3H, s);MS(ESI): 473 (MH⁺).

EXAMPLE 20 Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoicAcid, Methyl Ester

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with methyl 3-aminobenzoate. ¹H-NMR(CDCl₃): δ 7.80 (1H, m), 7.68 (1H, m), 7.56-7.60 (2H, m), 7.49 (1H, dd),7.42 (1H, m), 7.27-7.36 (4H, m), 7.14-7.20 (2H, m), 7.01 (1H, d), 5.16(2H, s), 3.92 (3H, s), 3.71 (3H, s); MS(ESI): 488 (MH⁺).

EXAMPLE 21 Preparation of3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(pyridin-3-ylimino)-thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 3-aminopyridine. ¹H-NMR (CDCl₃): δ8.37 (1H, dd), 8.35 (1H, dd), 7.56-7.60 (2H, m), 7.51 (1H, dd),7.27-7.37 (6H, m), 7.18 (1H, m), 7.04 (1H, d), 5.16 (2H, s), 3.73 (3H,s); MS(ESI): 431 (MH⁺).

EXAMPLE 22 Preparation ofN-{3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethoxyphenyl}acetamide

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with N-(4-amino-3-ethoxyphenyl)acetamide.¹H-NMR (CDCl₃): δ 7.63 (2H, d), 7.48 (1H, d), 7.28-7.36 (5H, m), 7.15(1H, t), 7.10 (1H, s), 7.00 (1H, d), 6.96 (1H, d), 6.91 (1H, d), 5.18(2H, s), 3.97 (2H, q), 3.70 (3H, s), 2.16 (3H, s), 1.33 (3H, t);MS(ESI): 531 (MH⁺).

EXAMPLE 23 Preparation of3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(pyridin-4-ylimino)-thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4-aminopyridine. ¹H-NMR (CDCl₃): δ8.53 (2H, dd), 7.56 (2H, m), 7.52 (1H, dd), 7.28-7.38 (4H, m), 7.19 (1H,m), 7.06 (1H, d), 6.93 (2H, dd), 5.14 (2H, s), 3.75 (3H, s); MS(ESI):431 (MH⁺).

EXAMPLE 24 Preparation of4-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoicAcid, Methyl Ester

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with methyl 4-aminobenzoate. ¹H-NMR(CDCl₃): δ 8.04 (2H, m), 7.58 (2H, m), 7.50 (1H, d), 7.27-7.38 (4H, m),7.17 (1H, t), 7.01-7.08 (3H, m), 5.15 (2H, s), 3.92 (3H, s), 3.72 (3H,s); MS(ESI): 488 (MH⁺).

EXAMPLE 25 Preparation of3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-[4-(trifluoro-methoxy)phenylimino]thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4-(trifluoromethoxy)aniline. ¹H-NMR(CDCl₃): δ 7.57 (2H, m), 7.50 (1H, dd), 7.27-7.36 (4H, .m), 7.14-7.22(3H, m), 7.03 (1H, d), 7.00 (2H, dd), 5.14 (2H, s), 3.75 (3H, s);MS(ESI): 514 (MH⁺).

EXAMPLE 26 Preparation of3-Benzyl-2-(1H-indazol-5-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 5-aminoindazole. ¹H-NMR (CDCl₃): δ10.05 (1H, br s), 8.08 (1H, d), 7.64-7.67 (2H, m), 7.51-7.55 (2H, m),7.32-7.41 (5H, m), 7.20 (1H, m), 7.14 (1H, dd), 7.04 (1H, d), 5.23 (2H,s), 3.74 (3H, s); MS(ESI): 470 (MH⁺).

EXAMPLE 27 Preparation of3-Benzyl-2-(4-imidazol-1-ylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4-(1H-imidazol-1-yl)aniline. ¹H-NMR(CDCl₃): δ 7.93 (1H, s), 7.66 (2H, d), 7.58 (1H, d), 7.35-7.46 (7H, m),7.29 (1H, s), 7.25 (1H, t), 7.18 (2H, m), 7.11 (1H, d), 5.24 (2H, s),3.82 (3H, s); MS(ESI): 496 (MH⁺).

EXAMPLE 28 Preparation of2-(Benzo[1,3]dioxol-5-ylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 3,4-(methylenedioxy)aniline. ¹H-NMR(CDCl₃): δ 7.56-7.60 (2H, m), 7.49 (1H, dd), 7.28-7.36 (4H, m), 7.16(1H, m), 7.02 (1H, d), 6.80 (1H, d), 6.56 (1H, d), 6.48 (1H, dd), 5.98(2H, s), 5.14 (2H, s), 3.75 (3H, s); MS(ESI): 474 (MH⁺).

EXAMPLE 29 Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoicAcid

An aqueous solution of lithium hydroxide (1 M, 5 mL) was added to asolution of compound I-20 (0.13 g, 0.27 mmol) in THF (20 mL). Afterstirring at room temperature for 12 h, the reaction mixture wasconcentrated under reduced pressure. The resulting residue was acidifiedwith hydrochloric acid (1 M, 10 mL) and extracted with EtOAc. Thecombined organic extracts were dried (anhydrous magnesium sulfate),concentrated under reduced pressure and chromatographed (silica gel,MeOH/DCM, 1:19) to yield the title compound (0.12 g, 95%) as a yellowsolid. ¹H-NMR (MeOD-d₃): δ 7.81 (1H, d), 7.63-7.68 (2H, m), 7.55 (1H,d), 7.50 (2H, d), 7.44 (1H, t), 7.31-7.40 (3H, m), 7.28 (1H, d),7.16-7.23 (3H, m), 5.15 (2H, s), 3.79 (3H, s); MS(ESI): 474 (MH⁺).

EXAMPLE 30 Preparation of N-Ethyl-1,2-phenylenediamine

N-Ethyl-2-nitroaniline (0.97 g, 5.8 mmol) was dissolved in EtOAc (60 mL)and placed in a closed vessel. 10% Pd/C (0.4 g, 7 mol %) was added andthe mixture was hydrogenated under 50 psi H₂ for 2 h. The mixture wasfiltered through celite and the filtrate was concentrated under reducedpressure to yield the title product (0.79 g, 99%) as a brown liquid,which was used without further purification. ¹H-NMR (CDCl₃): δ 6.83 (1H,m), 6.64-6.74 (3H, m), 3.29 (3H, br s), 3.15 (2H, q), 1.30 (3H, t); TLC(2:98 MeOH/DCM R_(f) 0.24).

Preparation of3-Benzyl-2-[2-(ethylamino)phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one

The title compound was then prepared in a manner similar to thatdescribed in Example 1 by replacing aniline withN-ethyl-1,2-phenylenediamine. ¹H-NMR (CDCl₃): δ 7.47-7.54 (3H, m),7.30-7.37 (3H, m), 7.28 (1H, m), 7.17 (1H, t), 7.00-7.06 (2H, m), 6.96(1H, dd), 6.64 (1H, m), 6.60 (1H, d), 5.19 (2H, s), 3.76 (3H, s), 3.68(1H, br s), 3.01 (2H, q), 1.05 (3H, t); MS(ESI): 473 (MH⁺).

EXAMPLE 31 Preparation of 4-Methylamino-3-nitrobenzonitrile

4-Fluoro-3-nitrobenzonitrile (0.25 g, 1.5 mmol) was cautiously added toa solution of methylamine (2.0 M, 5.0 mL) in THF. The mixture wasstirred at room temperature for 8 h, concentrated under reducedpressure, and chromatographed (silica gel, DCM) to give the titleproduct (0.18 g, 68%) as a yellow solid. ¹H-NMR (CDCl₃): δ 8.52 (1H, d),8.41 (1H, br s), 7.64 (1H, dd), 6.92 (1H, d), 3.10 (3H, d).

Preparation of 3-Amino-4-methylamino)benzonitrile

4-Methylamino-3-nitrobenzonitrile (0.18 g, 1.0 mmol) was dissolved inEtOAc (10 mL) and placed in a closed vessel. 10% Pd/C (50 mg, 5 mol %)was added and the mixture was hydrogenated via a hydrogen-filled balloonthat was affixed to the vessel. After 2 h the mixture was filteredthrough celite and the filtrate was concentrated under reduced pressureto yield the title product (0.14 g, 93%) as an off-white solid, whichwas used without further purification. ¹H-NMR (CDCl₃): δ 7.19 (1H, dd),6.92 (1H, d), 6.57 (1H, d), 4.04 (1H, br s), 3.30 (2H, br s), 2.91 (3H,br s); TLC (5:95 MeOH/DCM R_(f) 0.33).

Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(methylamino)benzonitrile

The title compound was then prepared in a manner similar to thatdescribed in Example 1 by replacing aniline with3-amino-4-methylamino)benzonitrile. ¹H-NMR (CDCl₃): δ 7.55 (1H, d),7.42-7.47 (2H, m, 7.34-7.41 (3H, m), 7.28-7.34 (2H, m), 7.21 (1H, m),7.18 (1H, d), 7.11 (1H, d, 6.45 (1H, d), 5.17 (2H, s), 4.15 (1H, br s),3.83 (3H, s), 2.63 (3H, br s); MS(ESI): 484 (MH⁺).

EXAMPLE 32 Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(ethylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with ethylamine. ¹H-NMR (CDCl₃): δ7.54 (1H, d), 7.41-7.46 (2H, m), 7.27-7.40 (5H, m), 7.18-7.24 (2H, m),7.11 (1H, d), 6.49 (1H, d), 5.18 (2H, s), 4.23 (1H, t), 3.83 (3H, s),3.01 (2H, m), 1.02 (3H, t); MS(ESI): 498 (MH⁺).

EXAMPLE 33 Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(isopropylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with isopropylamine. ¹H-NMR (CDCl₃):δ 7.54 (1H, d), 7.45 (2H, d), 7.27-7.40 (5H, m), 7.18-7.24 (2H, m), 7.11(1H, d), 6.53 (1H, d), 5.18 (2H, s), 4.29 (1H, d), 3.83 (3H, s), 3.54(1H, m), 1.02 (6H, d); MS(ESI): 512 (MH⁺).

EXAMPLE 34 Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(dimethylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with dimethylamine. ¹H-NMR (CDCl₃):δ 7.49-7.53 (3H, m), 7.27-7.37 (5H, m), 7.18 (1H, t), 7.13 (1H, d), 7.06(1H, d), 6.85 (1H, d), 5.18 (2H, s), 3.76 (3H, s), 2.68 (6H, s);MS(ESI): 498 (MH⁺).

EXAMPLE 35 Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(tert-butylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with tert-butylamine. ¹H-NMR(CDCl₃): δ 7.54 (1H, d), 7.44 (2H, d), 7.27-7.40 (5H, m), 7.18-7.24 (2H,m), 7.11 (1H, d), 6.80 (1H, d), 5.18 (2H, s), 4.67 (1H, br s), 3.83 (3H,s), 1.22 (9H, s); MS(ESI): 526 (MH⁺).

EXAMPLE 36 Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(2,2,2-trifluoroethylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with 2,2,2-trifluoroethylamine.¹H-NMR (CDCl₃): δ 7.57 (1H, d), 7.27-7.44 (8H, m), 7.23 (1H, t), 7.14(1H, d), 6.62 (1H, d), 5.17 (2H, s), 4.49 (1H, t), 3.86 (3H, s), 3.50(2H, m); MS(ESI): 552 (MH⁺).

EXAMPLE 37 Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-piperidin-1-ylbenzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with piperidine. ¹H-NMR (CDCl₃): δ7.50-7.54 (3H, m), 7.27-7.37 (5H, m), 7.18 (1H, t), 7.15 (1H, d), 7.05(1H, d), 6.92 (1H, d), 5.17 (2H, s), 3.75 (3H, s), 2.98 (4H, m), 1.44(6H, m); MS(ESI): 538 (MH⁺).

EXAMPLE 38 Preparation of2-[5-Acetyl-2-(ethylamino)phenylimino]-3-benzyl-5-(3-ethyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with ethylamine and by replacing4-fluoro-3-nitrobenzonitrile with 4′-chloro-3′-nitroacetophenone. ¹H-NMR(CDCl₃): δ 7.68 (1H, dd), 7.65 (1H, d), 7.53 (1H, d), 7.45-7.49 (2H, m),7.32-7.38 (3H, m), 7.28-7.31 (1H, m), 7.19 (1H, m), 7.06 (1H, d), 6.52(1H, d), 5.19 (2H, s), 4.24 (1H, t), 3.78 (3H, s), 3.06 (2H, m), 2.51(3H, s), 1.05 (3H, t); MS(ESI): 515 (MH⁺).

EXAMPLE 39 Preparation of3-Ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-thioxothiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing N-benzyl rhodanine with N-ethyl rhodanine. ¹H-NMR(CDCl₃): δ 7.63 (1H, d), 7.45 (1H, m), 7.30 (1H, m), 7.22 (1H, d), 4.24(2H, q), 3.91 (3H, s), 1.32 (3H, t); MS(ESI): 309 (MH⁺).

Preparation3-Ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate

The title compound was prepared from3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-thioxothiazolidin-4-oneand methyl p-toluenesulfonate in a manner similar to that described inExample 1. ¹H-NMR (CDCl₃): δ 7.82 (1H, d), 7.77 (2H, d), 7.58-7.66 (2H,m), 7.49 (1H, m), 7.08 (2H, d), 4.52 (3H, s), 4.21 (2H, q), 3.29 (3H,s), 2.29 (3H, s), 1.45 (3H, t).

Preparation of3-Ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-6-ylimino)-thiazolidin-4-one

The title compound was prepared from3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate and 6-aminoquinoline in a manner similar to thatdescribed in Example 1. ¹H-NMR (CDCl₃): δ 8.85 (1H, dd), 8.11 (1H, d),8.10 (1H, d), 7.51 (1H, dd) 7.46 (1H, dd), 7.40 (1H, d), 7.38 (1H, dd),7.32 (1H, m), 7.16 (1H, m), 7.01 (1H, d), 4.10 (2H, q), 3.70 (3H, s),1.41 (3H, t); MS(ESI): 419 (MH⁺).

EXAMPLE 40 Preparation of3-Ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-morpholin-4-yl-phenylimino)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 39 by replacing 6-aminoquinoline with 4-morpholin-4-ylaniline.¹H-NMR (CDCl₃): δ 7.49 (1H, dd), 7.31 (1H, m), 7.15 (1H, m), 6.91-7.02(5H, m), 4.03 (2H, q), 3.88 (4H, m), 3.73 (3H, s), 3.17 (4H, m), 1.36(3H, t); MS(ESI): 453 (MH⁺).

EXAMPLE 41 Preparation of3-[3-Ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(methylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 39 by replacing 6-aminoquinoline with3-amino-4-(methylamino)benzonitrile. ¹H-NMR (CDCl₃): δ 7.53 (1H, d),7.36 (1H, m), 7.36 (1H, dd), 7.25 (1H, m), 7.20 (1H, m), 7.09 (1H, d),6.60 (1H, d), 4.86 (1H, q), 4.07 (2H, q), 3.81 (3H, s), 2.92 (3H, d),1.37 (3H, t); MS(ESI): 422 (MH⁺).

EXAMPLE 42 Preparation of4-Dimethylamino-3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 39 by replacing 6-aminoquinoline with3-amino-4-(dimethylamino)benzonitrile. ¹H-NMR (CDCl₃): δ 7.52 (1H, dd),7.34 (1H, m), 7.34 (1H, dd), 7.20 (1H, d), 7.18 (1H, m), 7.06 (1H, d),6.92 (1H, d), 4.08 (2H, q), 3.76 (3H, s), 2.90 (6H, s), 1.38 (3H, t);MS(ESI): 436 (MH⁺).

EXAMPLE 43 Preparation of4-Ethylamino-3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 39 by,replacing 6-aminoquinoline with3-amino-4-(ethylamino)benzonitrile. ¹H-NMR (CDCl₃): δ 7.53 (1H, d),7.32-7.40 (2H, m), 7.26 (1H, m), 7.20 (1H, m), 7.10 (1H, d), 6.60 (1H,d), 4.75 (1H, t), 4.08 (2H, q), 3.81 (3H, s), 3.22 (2H, m), 1.37 (3H,t), 1.29 (3H, t); MS(ESI): 436 (MH⁺).

EXAMPLE 44 Preparation of3-[3-Ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(isopropylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 39 by replacing 6-aminoquinoline with3-amino-4-(isopropylamino)benzonitrile. ¹H-NMR (CDCl₃): δ 7.53 (1H, dd),7.36 (1H, m), 7.32 (1H, dd), 7.25 (1H, d), 7.20 (1H, m), 7.10 (1H, d),6.60 (1H, d), 4.74 (1H, d), 4.08 (2H, q), 3.81 (3H, s), 3.67 (1H, m),1.37 (3H, t), 1.25 (6H, d); MS(ESI): 450 (MH⁺).

EXAMPLE 45 Preparation of3-(3-Butyl-4-oxothiazolidin-2-ylideneamino)benzonitrile

To a 250 mL flask was added 3-aminobenzonitrile (0.59 g, 5.0 mmol),CHCl₃ (25 mL) and saturated sodium bicarbonate (25 mL). To thewell-stirred mixture was added dropwise thiophosgene (0.39 mL, 5.1mmol). After 2 h butylamine (0.50 mL, 5.1 mmol) was added dropwise andstirred 1 h. The reaction mixture was then extracted with CHCl₃,concentrated under reduced pressure, and chromatographed (silica gel,2:98 MeOH/DCM) to yield 1-butyl-3-(3-cyanophenyl)thiourea (1.02 g, 87%)as a white solid: TLC (2:98 MeOH/DCM R_(f) 0.47).

To a 100 mL flask was added anhydrous EtOH (25 mL),1-butyl-3-(3-cyanophenyl)thiourea (0.99 g, 4.2 mmol), ethylchloroacetate (0.51 mL, 5.0 mmol), and anhydrous pyridine (0.5 mL, 5mmol). After heating under reflux 16 h, the product mixture wasconcentrated under reduced pressure and chromatographed (silica gel,2:98 MeOH/DCM) to afford the title product (0.78 g, 67%) as a colorlessoil. ¹H-NMR (CDCl₃): δ 7.40-7.47 (2H, m), 7.25 (1H, m), 7.19 (1H, m),3.84 (2H, t), 3.84 (2H, s), 1.69 (2H, m), 1.39 (2H, m), 0.97 (3H, t);MS(ESI): 274 (MH⁺).

Preparation of3-[3-Butyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

To a 8 mL vial was added3-(3-butyl-4-oxothiazolidin-2-ylideneamino)benzonitrile (55 mg, 0.20mmol), 3-methyl-2-(methylthio)benzothiazol-3-ium p-toluenesulfonate (73mg, 0.20 mmol), anhydrous MeCN (2 mL) and TEA (70 μL, 0.50 mmol). Thereaction mixture was first Warmed to 50° C. and the resulting solutionwas allowed to stir at room temperature for 16 h. The product mixturewas concentrated under reduced pressure, chromatographed (silica gel,1:99 MeOH/DCM) and then recrystallized from MeCN to give the titleproduct (11.8 mg) as a yellow solid. ¹H-NMR (CDCl₃): δ 7.52 (1H, dd),7.38-7.48 (2H, m), 7.32-7.37 (2H, m), 7.25 (1H, m), 7.18 (1H, m), 7.06(1H, d), 3.96 (2H, t), 3.75 (3H, s), 1.77 (2H, m), 1.44 (2H, m), 0.98(3H, t); MS(ESI): 421 (MH⁺).

EXAMPLE 46 Preparation of3-Benzyl-5-(3-methyl-3H-benzoxazol-2-ylidene)-2-thioxothiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing 2-(methylthio)benzothiazole with2-mercaptobenzoxazole. ¹H-NMR (CDCl₃): δ 7.49 (2H, d), 7.24-7.41 (6H,m), 7.18 (1H, d), 5.31(2H, s), 4.17 (3H, s); MS(ESI): 377 (MNa⁺).

Preparation of3-Benzyl-5-(3-methyl-3H-benzoxazol-2-ylidene)-2-(quinolin-5-ylimino)-thiazolidin-4-one

To a 10 mL flask was added3-benzyl-5-(3-methyl-3H-benzoxazol-2-ylidene)-2-thioxothiazolidin-4-one(100 mg, 0.28 mmol), anhydrous CHCl₃ (2 mL) and methylp-toluenesulfonate (53 μL, 0.35 mmol). After heating at reflux 10 min,the reaction mixture was heated at 120° C. for 2 h to yield a red oil.The desired intermediate,3-benzyl-5-(3-methyl-3H-benzoxazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate, was not isolated successfully in previousexperiments similar to Example 1 and, thus, the crude reaction mixturewas diluted with anhydrous CHCl₃ (4 mL) and used without purification inthe next step.

To a 8 mL vial was added the crude reaction mixture (2 mL) and5-aminoquinoline (29 mg, 0.20 mmol). After warming the mixture to 55°C., TEA (0.10 mL, 0.56 mmol) was added and the mixture was heated at 60°C. for 16 h. After cooling to room temperature, the resulting productmixture was concentrated under reduced pressure and chromatographed(silica gel, 2:98 MeOH/DCM) to yield the title product (21 mg) as ayellow solid. ¹H-NMR (CDCl₃): δ 8.86 (1H, dd), 7.97 (1H, dd), 7.85 (1H,d), 7.66 (1H, dd), 7.56 (2H, m), 7.30-7.42 (3H, m), 7.19-7.25 (3H, m),7.11-7.17 (2H, m), 7.05 (1H, d), 5.24 (2H, s), 4.11 (3H, s); MS(ESI):465 (MH⁺).

EXAMPLE 47 Preparation of3′-Benzyl-3-methyl-4-phenyl-2′-thioxo-2′,3′-dihydro-3H-[2,5′]bithiazol-yliden-4′-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing 2-(methylthio)benzothiazole with2-mercapto-4-phenylthiazole. ¹H-NMR (CDCl₃): δ 7.49-7.56 (5H, m),7.34-7.38 (2H, m), 7.24-7.33 (3H, m), 6.54 (1H, s), 5.39 (2H, s), 3.68(3H, s); MS(ESI): 397 (MH⁺).

Preparation3′-Benzyl-3-methyl-2′-methylthio-4′-oxo-4-phenyl-3H,4′H-[2,5′]bithiazol-yliden-3′-iump-Toluenesulfonate

The title compound was prepared from3′-benzyl-3-methyl-4-phenyl-2′-thioxo-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-oneand methyl p-toluenesulfonate in a manner similar to that described inExample 1. ¹H-NMR (CDCl₃): δ 7.72 (2H, d), 7.49-7.56 (3H, m), 7.42-7.47(2H, m), 7.36-7.41 (5H, m), 7.05 (2H, d), 6.99 (1H, s), 5.29 (2H, s),4.26 (3H, s), 3.14 (3H, s), 2.29 (3H, s).

Preparation ofN-[4-(3′-Benzyl-3-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]-bithiazolyliden-2′-ylideneamino)phenyl]acetamide

The title compound was prepared from3′-benzyl-3-methyl-2′-methylthio-4′-oxo-4-phenyl-3H,4′H-[2,5′]bithiazolyliden-3′-iump-toluenesulfonate and 4′-aminoacetanilide in a manner similar to thatdescribed in Example 1. ¹H-NMR (CDCl₃): δ 7.56 (2H, d), 7.42-7.47 (5H,m), 7.24-7.34 (5H, m), 7.12 (1H, s), 6.97 (2H, d), 6.30 (1H, s), 5.15(2H, s), 3.49 (3H, s), 2.17 (3H, s); MS(ESI): 513 (MH⁺).

EXAMPLE 48 Preparation of2′-[5-Acetyl-2-(ethylamino)phenylimino]-3′-benzyl-3-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 47 by replacing 4′-aminoacetanilide with3′-amino-4′-(ethylamino)acetophenone. ¹H-NMR (CDCl₃): δ 7.63-7.67 (2H,m), 7.44-7.48 (5H, m), 7.27-7.37 (5H, m), 6.50 (1H, d), 6.37 (1H, s),5.20 (2H, s), 4.29 (1H, t), 3.55 (3H, s), 3.05 (2H, m), 2.49 (3H, s),1.04 (3H, t); MS(ESI): 541 (MH⁺).

EXAMPLE 49 Preparation of3-(3′-Benzyl-3-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazol-yliden-2′-ylideneamino)-4-(ethylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 47 by replacing 4′-aminoacetanilide with3-amino-4-(ethylamino)benzonitrile. ¹H-NMR (CDCl₃): δ 7.46-7.50 (3H, m),7.41-7.45 (2H, m), 7.23-7.40 (6H, m), 7.21 (1H, d), 6.47 (1H, d), 6.40(1H, s), 5.18 (2H, s), 4.27 (1H, t), 3.59 (3H, s), 3.00 (2H, m), 1.01(3H, t); MS(ESI): 524 (MH⁺).

EXAMPLE 50 Preparation ofN-[4-(3′-Benzyl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)phenyl]acetamide

The title compound was prepared in a manner similar to that described inExample 47 by replacing 2-mercapto-4-phenylthiazole with2-mercaptothiazole. ¹H-NMR (CDCl₃): δ 7.55 (2H, d), 7.44 (2H, d),7.24-7.33 (3H, m), 7.13 (1H, s), 6.95 (2H, d), 6.52 (1H, d), 6.37 (1H,d), 5.12 (2H, s), 3.68 (3H, s), 2.17 (3H, s); MS(ESI): 437 (MH⁺).

EXAMPLE 51 Preparation ofN-[4-(3′-Benzyl-3-methyl-4′-oxo-[2,5′]bithiazolidinyliden-2′-ylidene-amino)phenyl]acetamide

The title compound was prepared in a manner similar to that described inExample 47 by replacing 2-mercapto-4-phenylthiazole with2-methylthio-2-thiazoline. ¹H-NMR (CDCl₃): δ 7.53 (2H, d), 7.44 (2H, d),7.23-7.32 (3H, m), 7.14 (1H, s), 6.93 (2H, d), 5.07 (2H, s), 3.63 (2H,t), 3.16 (3H, s), 3.09 (2H, t), 2.17 (3H, s); MS(ESI): 439 (MH⁺).

EXAMPLE 52 Preparation of 1-Benzyl-345-cyano-2-ethylaminophenyl)thiourea

To a 100 mL flask was added 3-amino-4-(ethylamino)benzonitrile (1.0 g,6.2 mmol), anhydrous THF (50 mL) and benzylisothiocyanate (0.92 g, 6.2mmol). The reaction mixture was heated at 50° C. with stirring for 6 h.After cooling to room temperature, the reaction mixture was concentratedunder reduced pressure and chromatographed (silica gel, 1:1 EtOAc/Hex)to yield the title product (1.78 g, 93 %). ¹H-NMR (CDCl₃): δ 7.48 (1H,dd), 7.37 (1H, d), 7.31 (3H, m), 7.24 (1H, s), 7.18 (1H, br), 6.67 (1H,d), 5.95 (1H, br), 4.81 (2H, d), 4.68 (1H, br), 3.19 (2H, m), 1.23 (3H,t).

Preparation of3-(3-Benzyl-4-oxothiazolidin-2-ylideneamino)-4-ethylamino)benzo-nitrile

To a 100 mL flask was added1-benzyl-3-(5-cyano-2-ethylaminophenyl)thiourea (1.0 g, 3.2 mmol),anhydrous ethanol (40 mL), ethyl chloroacetate (0.39 g, 3.2 mmol) andthen DBU (0.58 g, 3.8 mmol). The reaction was heated at 80° C. for 30min. After cooling to room temperature, the reaction mixture wasconcentrated under reduced pressure and chromatographed (silica gel, 1:1EtOAc/Hex) to afford the title product (0.98 g, 87%). ¹H-NMR (CDCl₃): δ7.38 (6H, m), 7.11 (1H, d), 6.50 (1H, d), 5.05 (2H, s), 3.96 (2H, s),3.01 (2H, m), 1.03 (3H, t).

Preparation of 3,5-Dimethyl-4-phenyl-3H-thiazole-2-thione

To a 100 mL flask was added freshly prepared triethylammoniummethydithiocarbamate (2.0 g, 9.5 mmol), anhydrous MeCN (50 mL), and2-bromopropiophenone (2.04 g, 9.5 mmol). The reaction mixture wasstirred at room temperature for 3 h. The reaction mixture wasconcentrated under reduced pressure and the resulting crude residue wastreated with conc H₂SO₄ (5 mL) with stirring at room temperature. After20 min, the reaction mixture was diluted with water (75 mL) and thenmixed with DCM (75 mL). The layers were separated and the aqueous layerextracted once more with DCM (75 mL). The combined organic layers werewashed with water (3×50 mL) and then brine (50 mL), dried over anhydrousMgSO₄ and concentrated under reduced pressure to afford the titleproduct (1.95 g, 92%) as an off-white solid, which was used withoutfurther purification. ¹H-NMR (CDCl₃): δ 7.50 (2H, m), 7.27 (2H,m), 3.45(3H, s), 2.06 (3H, s).

Preparation of3-(3′-Benzyl-3,5-dimethyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]-bithiazolyliden-2′-ylideneamino)-4-(ethylamino)benzonitrile

To an 8 mL vial was added 3,5-dimethyl-4-phenyl-3H-thiazole-2-thione(100 mg, 0.45 mmol), methyl p-toluenesulfonate (126 mg, 0.68 mmol) andanhydrous anisole (0.5 mL). The reaction was heated to 120° C. andstirred for 3 h. The cooled reaction mixture was diluted with anhydrousMeCN (3 mL) and then treated with3-(3-benzyl-4-oxothiazolidin-2-ylideneamino)-4-(ethylamino)benzonitrile(50 mg, 0.14 mmol) and TEA (70 μL, 0.50 mmol). The reaction mixture waswarmed to 80° C. and the resulting solution was allowed to stir for 16h. The product mixture was concentrated under reduced pressure andchromatographed (silica gel, 1:1 EtOAc/Hex) to yield the title product(48.3 mg, 64%) as a yellow solid. ¹H-NMR (CDCl₃): δ 7.40 (5H, m) 7.33(2H, m), 7.25 (3H, m), 7.23 (2H, m), 6.46 (1H, d), 5.15 (2H, s), 4.28(1H, m), 3.46 (3H, s), 2.99 (2H, m), 2.28 (3H, s), 1.01 (3H, t);MS(ESI): 538 (MH⁺).

EXAMPLE 53 Time Resolved Fluorescence Resonance Energy Transfer(TR-FRET) Assay

The FRET assay was performed by incubating 8 nM of GST-FXR-LBD, 8 nM ofEuropium-labeled anti-GST antibody (Wallac), 16 nM biotin-SRC-1 peptide[5′-biotin-CPSSHSSLTERHKILHRLLQEGSPS-CONH2], 20 nM APC-SA[allophycocyanin conjugated streptavidin] (Wallac) in FRET assay buffer(20 mM KH₂PO₄/K₂HPO₄ (pH 7.3), 150 mM NaCl, 2 mM CHAPS, 2 mM EDTA, 1 mMDTT) in the presence of the test compound(s) for 2-4 hours at roomtemperature. Data was collected using an LJL Analyst with readings at615 nm and 665 nm.

EXAMPLE 54 FXR Co-transfection Assay

The basic co-transfection protocol for measuring FXR activity is asfollows. CV-1 African Green Monkey Kidney cells are plated 24 hoursbefore transfection to achieve approximately 70-80 percent confluency.Cells are transfected with CMX-hFXR, CMX-RXRα, Luc12 reporter(ECREx7-Tk-Luciferase), and a CMX-β-Galactosidase expression vector. Thetransfection reagent used is DOTAP. Cells are incubated with theDOTAP/DNA mixture for 5 hours after which the cells are harvested andplated onto either 96 well or 384 well plates containing the appropriateconcentration of test compound. The assay is allowed to continue for anadditional 18-20 hours, after which the cells are lysed, and theluciferase activity is measured on a standard plate reader.

Results of Examples 53 and 54

Both the FXR/ECREx7 co-transfection assay (Example 54) and the TR-FRETassay (Example 53) can be used to establish the EC₅₀/IC₅₀ values forpotency and percent activity or inhibition for efficacy. Efficacydefines the activity of a compound relative to a high control(chenodeoxycholic acid, CDCA) or a low control (DMSO/vehicle). The doseresponse curves are generated from an 8 point curve with concentrationsdiffering by ½ LOG units. Each point represents the average of 4 wellsof data from a 384 well plate. The curve for the data is generated byusing the equation:

Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((LogEC50−X)*HillSlope))

The EC₅₀/IC₅₀ is therefore defined as the concentration at which anagonist or antagonist elicits a response that is half way between theTop (maximum) and Bottom (baseline) values. The EC₅₀/IC₅₀ valuesrepresented are the averages of at least 3 independent experiments. Thedetermination of the relative efficacy or % control for an agonist is bycomparison to the maximum response achieved by chenodeoxycholic acidthat is measured individually in each dose response experiment.

For the antagonist assay, 40 μM CDCA is added to each well of a 384 wellplate to elicit a response. The % inhibition for each antagonist istherefore a measurement of the inhibition of the activity of 40 μM CDCA.In this example 100% inhibition would indicate that the activity of 40μM CDCA has been reduced to baseline levels, defined as the activity ofthe assay in the presence of DMSO only.

Most of the compounds disclosed herein and tested exhibited activity inat least one of the above assays (EC₅₀ or IC₅₀ less than 10 μM). Mostshowed activity at below 1 μM. Some showed activity below 100 nM. Forexample,3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(ethylamino)benzonitrile(Example 32) shows an EC₅₀ of about 0.010 μM and a % efficacy of about150% in the co-transfection assay; and3-(3′-benzyl-3,5-dimethyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]-bithiazolyliden-2′-ylideneamino)-4-(ethylamino)benzonitrile(Example 52) shows an EC₅₀ of about 0.056 μM and a % efficacy of about32% in the co-transfection assay; and an IC₅₀ of about 0.042 μM and a %inhibition of about 48% in a FRET assay.

EXAMPLE 55 Preparation of3-{3-Benzyl-5-[3-methyl-5-(trifluoromethyl)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}4-(ethylamino)benzonitrile

To a suspension of 2-amino-4-(trifluoromethyl)benzenethiol hydrochloride(4.58 g, 20 mmol) in CHCl₃ (50 mL) was added satd aqueous Na₂CO₃ (50mL). To this stirred biphasic mixture was added CSCl₂ (1.57 mL, 20 mmol)dropwise. After the addition was complete, the mixture was stirred for72 h at 20° C. The organic layer was separated and the aqueous layer wasextracted by CHCl₃ (3×20 mL). The combined organic layer was washed bywater and dried over MgSO₄. Evaporation of solvent gave2-mercapto-5-(trifluoromethyl)benzothiazole (1.27 g), which was used inthe next step without further purification. ¹H-NMR (CDCl₃): δ 7.23 (1H,d), 6.94 (1H, s), 6.81 (1H, d), 4.53 (s, 1H).

To a suspension of the above compound in anisole (10 mL) was addedmethyl tosylate (MeOTs) (2.5 mL, 2 equiv) and the suspension was heatedto 130° C. for 3 h. After cooling to 20° C., acetonitrile and3-benzylrhodanine were added. To this suspension was added TEA (3 mL, 4equiv) dropwise, yellow precipitate appeared immediately. The suspensionwas stirred for 5 h at 20° C. The yellow solid was collected byfiltration and washed by acetonitrile and dried under high vacuum togive the product (360 mg).

To a suspension of the above compound in DMF (4 mL) was added MeOTs(0.45 mL, 3 equiv) and the resulted suspension was heated to 130° C. for5 h. After cooling to 20° C., acetone was added to precipitate theproduct. Solid was collected by filtration and washed by acetone anddried under high vacuum to afford the tosylate salt (110 mg).

A mixture of the above compound (56 mg, 0.1 mmol),3-amino-4-(ethylamino)benzonitrile (16 mg, 0.1 mmol) and TEA (28 μL, 0.2mmol) was shaken at 60° C. overnight. Evaporation of solvent gave acrude, which was purified by trituration with MeOH to afford the titlecompound (27 mg). ¹H-NMR indicated one isomer. ¹H-NMR (CDCl₃): δ 7.61(1H, d), 7.44 (2H, m), 7.35 (2H, m), 7.27-7.31 (4H, m), 7.18 (1H), 6.5(1H), 5.19 (2H, s), 4.19 (1H, t), 3.84 (3H, s), 3.01 (2H, m), 1.03 (3H,t); MS (ESI): 566 (MH⁺).

EXAMPLE 56 Preparation of3-[3-Benzyl-5-(3-methyl-5-methoxy-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(ethylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 55 by starting from 2-mercapto-5-methoxy-benzothiazole. ¹H-NMRindicated one isomer. ¹H-NMR (DMSO-d₃): δ 7.47 (1H, d), 7.13-7.21 (5H,m), 6.98 (1H, d), 6.86 (1H, d), 6.67 (1H, dd), 6.46 (1H, d), 4.96 (2H,s), 4.81 (1H, m), 3.66 (3H, s), 3.65 (3H, s), 2.89 (2H, m), 0.83 (3H,t); MS (ESI): 528 (MH⁺).

EXAMPLE 57 Preparation of3-[3-Benzyl-5-(5-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(ethylamino)benzonitrile

To a suspension of the product of Example 56 (1.06 g, 2 mmol) in DCM (10mL) was added BBr₃ (1.0 M in DCM, 2 mL) dropwise at −78° C. It waswarmed to 20° C. slowly and the suspension was stirred for 72 h at 20°C. under N₂. MeOH was added to decompose BBr₃ at 0° C. Solvent wasremoved to give a crude, which was purified by chromatography on silicagel eluting with MeOH-DCM (2.5:97.5) to afford the title compound (0.6g). ¹H-NMR indicated one isomer. ¹H-NMR (DMSO-d₆): δ 9.66 (1H, s), 7.35(1H, d), 7.13-7.24 (5H, m), 6.99 (1H, d), 6.60 (1H, d), 6.53 (1H, dd),6.46 (1H, d), 4.96 (2H, s), 4.82(1H, t), 3.58 (3H, s), 2.89 (2H, m),0.84 (3H, t); MS (ESI): 514 (MH⁺).

EXAMPLE 58 Preparation of Dimethylcarbamic Acid2-[3-Benzyl-2-(5-cyano-2-ethylamino-phenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-ylEster

To a suspension of the product of Example 57 in CHCl₃ was added TEA (84μL, 0.6 mmol) and dimethylcarbamoyl chloride (56 μL, 0.6 mmol). Theresulted suspension was heated to 65° C. overnight with shaking. Solventwas removed under vacuum to give a crude, which was purified bychromatography on silica gel, eluting by MeOH-DCM (5:95) to afford thetitle compound (38.6 mg). ¹H-NMR indicated one isomer. ¹H-NMR (DMSO-d₆):δ 97.73 (1H, d), 7.28-7.39 (7H, m), 7.14 (1H, d), 6.97 (1H, dd), 6.63(1H, dd), 5.12 (2H, s), 4.98 (1H, t), 3.78 (3H, s), 3.05 (6H, m), 2.91(3H, s), 0.99 (3H, t); MS (ESI): 585 (MH⁺).

EXAMPLE 59 Preparation of3-{3-Benzyl-5-[5-(2-hydroxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-(ethylamino)benzonitrile

To a solution of the product of Example 57 in DMF were added K₂CO₃ and3-bromoethanol and the resulting suspension was heated to 75° C. withstirring under nitrogen for 72 h. Solid was removed by filtration andwashed by DMF. Evaporation of solvent gave a crude, which was purifiedby chromatography on silica gel eluting with MeOH-DCM (5:95) to affordthe title compound (0.58 g). ¹H-NMR indicated one isomer. ¹H-NMR(DMSO-d₆): δ 7.62 (1H, d), 7.29-7.39 (5H, m), 7.14 (1H, d), 7.02 (1H,d), 6.84 (1H, dd), 5.75 (1H, d), 5.11 (2H, s), 4.97 (1H, t), 4.87 (1H,t), 4.05 (2H, t), 3.80 (3H, s, 3.71 (2H, m), 3.05 (2H, m), 0.99 (3H, t);MS (ESI): 558 (MH⁺).

EXAMPLE 60 Preparation of3-{3-Benzyl-5-[3-methyl-(2-morpholin-4-ylethoxy)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-(ethylamino)benzonitrile

To a suspension of the product of Example 59 (56 mg, 0.1 mmol) inanhydrous DCM (2 mL) was added triflic anhydride (Tf₂O) at −10° C. undernitrogen. The suspension was stirred for 1 h at −10° C. Morpholine (44μL, 0.5 mmol) was added and the reaction mixture was stirred overnightat 20° C. Evaporation of solvent gave a crude, which was purified bychromatography on silica gel eluting with MeOH-DCM to give the titlecompound (18 mg). ¹H-NMR indicated one isomer. ¹H-NMR (CDCl₃): δ 7.44(2H, m), 7.39 (1H, d), 7.32-7.36 (2H, m), 7.27-7.30 (2H, m), 7.20 (1H,d), 6.78 (1H, dd), 6.67 (1H, d), 6.49 (1H, d), 5.17 (2H, s), 4.22 (1H,t), 4.15 (2H, t), 3.78 (3H, s), 3.75 (4H, m), 3.01 (2 H, m), 2.83 (2H,t), 2.59 (2 H, t), 1.02 (3 H, t); MS (ESI): 627 (MH⁺).

EXAMPLE 613-[3-Benzyl-5-(1,3-dimethyl-1,3-dihydrobenzoimidazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(ethylamino)benzonitrile

To suspension of 2-mercaptobenzimidazole (15.02 g, 100 mmol) in aqueousNaHCO₃ (25.2 g, 300 mmol in 40 mL of H₂O) was added Me₂SO₄ (47.4 mL, 500mmol) dropwise at 20° C. A clear solution was obtained. The solution wasstirred for 17 h at 20° C. NaI (3.2 g, 200 mmol) was added. After thesolution was cooled in an ice-water bath, yellowish precipitateappeared. Solid was collected by filtration and washed by cold water andether. Drying under high vacuum afford the iodide salt (6.5 g).

To a solution of the above salt (66 mg, 0.2 mmol) and3-(3-benzyl-4-oxothiazolidin-2-ylideneamino)-4-(ethylamino)benzonitrile(70 mg, 0.2 mmol) in DMF was added DBU (62 mL, 2 equiv) and the solutionwas heated to 100° C. for 48 h. Evaporation of solvent under high vacuumgave a crude, which was purified by chromatography on silica gel elutingwith EtOAc-hexane (1:1) to give the title compound (3.6 mg). ¹H-NMRindicated one isomer. ¹H-NMR (CDCl₃): δ 7.46 (2H, m), 7.22-7.36 (8H, m),6.46 (1H,d), 5.17 (2H, s), 4.44 (1H, t), 3.79 (3H, s), 3.01 (2 H, m),0.88 (3 H, t); MS (ESI): 495 (MH⁺).

EXAMPLE 62 Preparation of3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-8-ylimino)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 8-aminoquinoline. MS(ESI): 481(MH⁺).

EXAMPLE 63 Preparation of3-Benzyl-2-(8-hydroxyquinolin-5-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 5-aminoquinolin-8-ol. MS(ESI): 497(MH⁺).

EXAMPLE 64 Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-butylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with butylamine. MS(ESI): 526 (MH⁺).

EXAMPLE 65 Preparation of4-Benzylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with benzylamine. MS(ESI): 560(MH⁺).

EXAMPLE 66 Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-cyclopentylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with cyclopentylamine. MS(ESI): 538(MH⁺).

EXAMPLE 67 Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(pyrrolidin-1-ylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with 1-aminopyrrolidine. MS(ESI):539 (MH⁺).

EXAMPLE 68 Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-pyrrolidin-1-ylbenzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with pyrrolidine. MS(ESI): 524(MH⁺).

EXAMPLE 69 Preparation of3-Benzyl-2-(isoquinolin-5-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 5-aminoisoquinoline. MS(ESI): 481(MH⁺).

EXAMPLE 70 Preparation of3-Benzyl-2-(isoquinolin-1-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 1-aminoisoquinoline. MS(ESI): 481(MH⁺).

EXAMPLE 71 Preparation ofN-{4-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}acetamide

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4′-aminoacetanilide. MS(ESI): 487(MH⁺).

EXAMPLE 72 Preparation of2-(4-Acetylphenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4′-aminoacetophenone. MS(ESI): 482(MH⁺).

EXAMPLE 73 Preparation of4-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzamide

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4-aminobenzamide. MS(ESI): 473(MH⁺).

EXAMPLE 74 Preparation of3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(naphthalen-1-ylimino)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 1-naphthylamine. MS(ESI): 480 (MH⁺).

EXAMPLE 75 Preparation of3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(naphthalen-2-ylimino)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 2-naphthylamine. MS(ESI): 480 (MH⁺).

EXAMPLE 76 Preparation of3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(pyridin-2-ylimino)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 1-aminopyridine. MS(ESI): 431 (MH⁺).

EXAMPLE 77 Preparation of4-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzenesulfonamide

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 4′-aminoacetophenone. MS(ESI): 509(MH⁺).

EXAMPLE 78 Preparation ofN-Acetyl-4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzenesulfonamide

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with N-acetyl-4-aminobenzenesulfonamide.MS(ESI): 551 (MH⁺).

EXAMPLE 79 A. Preparation of2-(3-Acetylphenylimino)-3-pyridin-3-ylmethylthiazolidin-4-one

The title compound was prepared from 3-picolyl isothiocyanatehydrobromide and 3′-aminoacetophenone in a manner similar to Example 52.¹H-NMR (CDCl₃): δ 8.80 (1H, d), 8.58 (1H, dd), 7.85 (1H, m), 7.74 (1H,m), 7.54 (1H, m), 7.45 (1H, m), 7.29 (1H, m), 7.15 (1H, m), 5.05 (2H,s), 3.86 (2H, s), 2.60 (3H, s).

B. Preparation of2-(3-Acetylphenylimino)-5-(3-methyl-3H-(benzothiazol-2-ylidene)-3-pyridin-3-ylmethylthiazolidin-4-one

The title compound was prepared from intermediate2-(3-acetylphenylimino)-3-pyridin-3-ylmethylthiazolidin-4-one and3-methyl-2-(methylthio)benzothiazol-3-ium p-toluenesulfonate asdescribed in Example 45. ¹H-NMR (CDCl₃): δ 8.87 (1H, d), 8.56 (1H, dd),7.93 (1H, m), 7.74 (1H, m), 7.60 (1H, m), 7.53 (1H, d), 7.46 (1H, m),7.27-7.38 (2H, m), 7.17-7.23 (2H, m), 7.05 (1H, d), 5.18 (2H, s), 3.74(3H, s), 2.62 (3H, s); MS(ESI): 473 (MH⁺).

EXAMPLE 80 A. Preparation of N-(5-Aminopyridin-2-yl)acetamide

To a hot solution of 2-amino-5-nitropyridine (1.4 g, 10 mmol) in aceticanhydride (5 mL) at 100° C. was added conc. H₂SO₄ (0.1 mL). Theresulting mixture was heated at 130° C. for 2 h, cooled and partitionedbetween EtOAc (200 mL) and water (100 mL). The layers were separated andthe aqueous layer was washed once with EtOAc (100 mL). The combinedorganic layers were washed with water (100 mL), saturated aqueous NaHCO₃(100 mL) and then brine (50 mL); dried over anhydrous MgSO₄ andconcentrated under reduced pressure to affordN-(5-nitropyridin-2-yl)acetamide (1.8 g, 98%), which was used withoutfurther purification. ¹H-NMR (CDCl₃): δ 9.14 (1H, d), 8.50 (1H, dd),8.40 (1H, d), 8.23 (1H, br s), 2.29 (3H, s).

B. Preparation ofN-{5-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]pyridin-2-yl}acetamide

In a manner similar to Example 30, intermediateN-(5-nitropyridin-2-yl)acetamide was hydrogenated and then condensedwith3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (DMSO-d₆): δ10.45 (1H, s), 8.07 (1H, d), 7.97 (1H, d), 7.75 (1H, d), 7.33-7.46 (7H,m), 7.29 (1H, m), 7.22 (1H, m), 5.06 (2H, s), 3.79 (3H, s), 2.09 (3H,s); MS(ESI): 488 (MH⁺).

EXAMPLE 81 Preparation ofN-{5-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-2-cyanophenyl}acetamide

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 5′-amino-2′-cyanoacetanilide.MS(ESI): 512 (MH⁺).

EXAMPLE 82 Preparation of2-(5-Acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-3-pyridin-3-ylmethylthiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 79 by replacing 3′-aminoacetophenone with3′-amino-4′-(ethylamino)acetophenone. MS(ESI): 516 (MH⁺).Recrystallization of the product from hot ethanol afforded crystalssuitable for single-crystal X-ray diffraction. Structural analysisshowed that the E-isomer had been obtained.

EXAMPLE 83 Preparation of4-Ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-pyridin-3-ylmethylthiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 79 by replacing 3′-aminoacetophenone with3-amino-4-(ethylamino)benzonitrile. MS(ESI): 499 (MH⁺).

EXAMPLE 84 Preparation of4-Ethylamino-3-[3-furan-2-ylmethyl-5-(3-methyl-3H-benzothbiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 83 by replacing 3-picolyl isothiocyanate hydrobromide with2-furfuryl isothiocyanate. MS(ESI): 488 (MH⁺).

EXAMPLE 85 Preparation of2-(5-Acetyl-2-methylaminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 31 by replacing 4-fluoro-3-nitrobenzonitrile with4′-chloro-3′-nitroacetophenone. MS(ESI): 501 (MH⁺).

EXAMPLE 86 Preparation ofN-{4-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2,2,2-trifluoroacetamide

The product of Example 4 was treated with trifluoroacetic anhydride inanhydrous DCM. After 1 h the product mixture was diluted with EtOAc,washed with water and satd aqueous NaHCO₃, dried over anhydrous Na₂SO₄and concentrated under reduced pressure to afford the title compound asa yellow solid. ¹H-NMR (CDCl₃): δ 7.81 (1H, br s), 7.53-7.59 (4H, m),7.49 (1H, d), 7.27-7.36 (4H, m), 7.17 (1H, m), 7.01-7.06 (3H, m), 5.15(2H, s), 3.73 (3H, s); MS(ESI): 541 (MH⁺).

EXAMPLE 87 A. Preparation of 4-Ethylamino-3-nitrobenzoic Acid MethylEster

In a manner similar to Example 31, 4-fluoro-3-nitrobenzoic acid wastreated with ethylamine to give 4-ethylamino-3-nitrobenzoic acid, whichwas then esterified with anhydrous hydrogen chloride in methanol to givethe title compound. ¹H-NMR (CDCl₃): δ 8.89 (1H, d), 8.28 (1H, br s),8.06 (1H, dd), 6.87 (1H, d), 3.90 (3H, s), 3.42 (2H, m), 1.40 (3H, t).

B. Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzoicAcid Methyl Ester

In a manner similar to Example 30, intermediate4-ethylamino-3-nitrobenzoic acid methyl ester was hydrogenated and thencondensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ 7.73(1H, dd), 7.65 (1H, d), 7.52 (1H, dd), 7.45-7.49 (2H, m), 7.27-7.38 (4H,m), 7.18 (1H, m), 7.06 (1H, d), 6.52 (1H, d), 5.19 (2H, s), 4.14 (1H, brt), 3.85 (3H, s), 3.78 (3H, s), 3.04 (2H, m), 1.04 (3H, t); MS(ESI): 531(MH⁺).

EXAMPLE 88 Preparation of4-Ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-phenethylthiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 83 by replacing 3-picolyl isothiocyanate hydrobromide withphenethyl isothiocyanate. MS(ESI): 512 (MH⁺).

EXAMPLE 89 Preparation of2-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoicAcid

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with anthranilic acid. MS(ESI): 474(MH⁺).

EXAMPLE 90 A. Preparation of 4-Ethylamino-3-nitrobenzoic Acid tert-ButylEster

4-Chloro-3-nitrobenzoic acid tert-butyl ester (3.0 g, 11.6 mmol),prepared according to a published procedure [WO 9707101], was cautiouslyadded to a solution of 2.0 M EtNH₂/THF (20 mL, 40 mmol) and TEA (2.0 mL,14 mmol) in anhydrous THF (30 mL). The resulting mixture was heated at65° C. for 3 h, cooled, concentrated under reduced pressure, dilutedwith DCM (200 mL), washed with water (2×100 mL) and brine (50 mL), driedover anhydrous Na₂SO₄ and concentrated to give the title compound (3.1g, 99%) as a yellow solid, which was used without further purification.¹H-NMR (CDCl₃): δ 8.80 (1H, d), 8.24 (1H, br s), 8.02 (1H, dd), 6.84(1H, d), 3.41 (2H, m), 1.59 (9H, s), 1.40 (3H, t).

B. Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzoicAcid tert-Butyl

In a manner similar to Example 30, intermediate4-ethylamino-3-nitrobenzoic acid tert-butyl ester was hydrogenated andthen condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ 7.69(1H, dd), 7.61 (1H, d), 7.52 (1H, dd), 7.45-7.49 (2H, m), 7.27-7.37 (4H,m), 7.18 (1H, m), 7.06 (1H, d), 6.51 (1H, d), 5.19 (2H, s), 4.11 (1H, brt), 3.79 (3H, s), 3.04 (2H, m), 1.57 (9H, s), 1.04 (3H, t); MS(ESI): 573(MH⁺).

EXAMPLE 91 Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzoicAcid

The product of Example 90 was treated with 55% TFA/DCM for 1 h,concentrated under reduced pressure, diluted with DCM, concentrated onceagain, diluted with DCM, allowed to stand over solid NaHCO₃, filteredand concentrated to afford the title product. MS(ESI): 517 (MH⁺).

EXAMPLE 92 Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(2-hydroxyethylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with 2-aminoethanol. ¹H-NMR (CDCl₃):δ 7.52 (1H, d), 7.42-7.49 (4H, m), 7.27-7.37 (4H, m), 7.19 (1H, m), 7.05(1H, d), 6.57 (1H, d), 5.94 (1H, br t), 5.19 (2H, s), 3.76 (3H, s), 3.48(2H, m), 3.03 (2H, q), 1.23 (3H, t), 1.04 (3H, t); MS(ESI): 514 (MH⁺).

EXAMPLE 93 Preparation of{2-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxdthiazolidin-2-ylideneamino]-4-cyanophenylamino}aceticAcid Methyl

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with glycine methyl ester. MS(ESI):542 (MH⁺).

EXAMPLE 94 A. Preparation of N-Ethyl-4-ethylamino-3-nitrobenzamide

In a manner similar to Example 31, the title compound was prepared from4-fluoro-3-nitrobenzoic acid (as a mixed anhydride) and ethylamine.¹H-NMR (CDCl₃): δ 8.52 (1H, d), 8.21 (1H, br s), 7.98 (1H, dd), 6.90(1H, d), 6.06 (1H, br s), 3.46-3.57 (2H, m), 3.38-3.45 (2H, m), 1.40(3H, t), 1.27 (3H, t).

B. Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-N-ethyl-4-ethylaminobenzamide

In a manner similar to Example 30, intermediateN-ethyl-4-ethylamino-3-nitrobenzamide was hydrogenated and thencondensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. MS(ESI): 544 (MH⁺).

EXAMPLE 95 Preparation of{2-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-cyanophenylamino}aceticAcid

The product of Example 93 was saponified under conditions similar tothat described in Example 29 to afford the title compound. MS(ESI): 528(MH⁺).

EXAMPLE 96 A. Preparation of 4-Ethylamino-3-nitropyridine

In a manner similar to example 31, the title compound was prepared from4-chloro-3-nitropyridine, prepared according to published procedure [J.Med. Chem. 1996, 39, 487-493], and ethylamine. ¹H-NMR (CDCl₃): δ 9.22(1H, s), 8.30 (1H, d), 8.10 (1H, br s), 6.71 (1H, d), 3.40 (2H, m), 1.39(3H, t).

B. Preparation of3-Benzyl-2-(4-ethylaminopyridin-3-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

In a manner similar to Example 30, intermediate4-ethylamino-3-nitropyridine was hydrogenated and then condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ8.04-8.09 (2H, m), 7.53 (1H, d), 7.44-7.48 (2H, m), 7.27-7.38 (4H, m),7.19 (1H, m), 7.07 (1H, d), 6.42 (1H, d), 5.19 (2H, s), 4.12 (1H, br t),3.79 (3H, s), 3.02 (2H, m), 1.05 (3H, t); MS(ESI): 474 (MH⁺).

EXAMPLE 97 A. Preparation of 3′-Fluoro-4′-nitroacetanilide

Added 3′-fluoroacetanilide (3.06 g, 20 mmol) cautiously to conc sulfuricacid (6 mL) at 5° C. To the resulting solution, added fuming nitric acid(1.05 mL, 25 mmol) dropwise while maintaining temperature at 5-10° C.After 30 min, added ice (50 g), later diluted with water (100 mL) andextracted with EtOAc (2×100 mL). The combined organic layers were washedwith saturated NaHCO₃ and brine, dried (Na₂SO₄) and concentrated to givethe crude product (4.0 g) as a mixture of isomers (1:1.4 ratio of4′-nitro/2′-nitro). The desired isomer, 3′-flouro-4′-nitroacetanilide,was isolated by flash chromatography (DCM-5% MeOH/DCM) in low yield (1.2g, 30%) as a yellow solid. ¹H-NMR (CDCl₃): δ 8.08 (1H, app t), 7.82 (1H,dd), 7.41 (1H, br s), 7.21 (1H, m), 2.25 (3H, s).

B. Preparation of 3′-Ethylamino-4′-nitroacetanilide

In a manner similar to Example 31, the title compound was prepared from3′-fluoro-4′-nitroacetanilide and ethylamine. ¹H-NMR (CDCl₃): δ 8.17(1H, br s), 8.13 (1H, d), 7.57 (1H, br d), 7.33 (1H, br s), 6.38 (1H,dd), 3.36 (2H, m), 2.22 (3H, s), 1.37 (3H, t).

C. Preparation ofN-{4-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-3-ethylaminophenyl}acetamide

In a manner similar to Example 30, intermediate3′-ethylamino-4′-nitroacetanilide was hydrogenated and then condensedwith3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ7.45-7.53 (3H, m), 7.27-7.37 (4H, m), 7.17 (1H, m), 7.03-7.09 (2H, m),6.91 (1H, d), 6.83 (1H, br d), 6.75 (1H, br s), 5.18 (2H, s), 3.78 (3H,s), 2.99 (2H, m), 2.15 (3H, s), 1.03 (3H, t); MS(ESI): 530 (MH⁺).

EXAMPLE 98 Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(2-dimethylaminoethylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExample 31 by replacing methylamine with N,N-dimethylethylenediamine.MS(ESI): 541 (MH⁺).

EXAMPLE 99 A. Preparation of N-Ethyl-3-ethylamino-4-nitrobenzamide

To a chilled solution (10° C.) of 3-fluoro4-nitrobenzoyl chloride (1.0g, 4.9 mmol) in anhydrous THF (30 mL) added dropwise 2.0 M solution ofethylamine in THF (10 mL, 20 mmol). After stirring 16 h at 25° C.,combine with satd NaHCO₃ (50 mL) and extracted with EtOAc (3×80 mL). Thecombined organic layers were washed with 1 N NaOH (50 mL) and brine (50mL), dried (MgSO₄) and concentrated under reduced pressure to yield thetitle compound (0.66 g, 57%) as an orange-yellow solid that was usedwithout further purification. ¹H-NMR (CDCl₃): δ 8.20 (1H, d), 7.98 (1H,br s), 7.36 (1H, d), 6.81 (1H, dd), 6.13 (1H, br s), 3.51 (2H, m), 3.42(2H, m), 1.39 (3H, t), 1.27 (3H, t).

B. Preparation of4-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-N-ethyl-3-ethylaminobenzamide

In a manner similar to Example 30, intermediateN-ethyl-3-ethylamino-4-nitrobenzamide was hydrogenated and thencondensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ7.46-7.54 (3H, m), 7.27-7.38 (4H, m), 7.19 (1H, m), 6.96-7.08 (4H, m),6.04 (1H, br t), 5.19 (2H, s), 3.76 (3H, s), 3.49 (2H, m), 3.06 (2H, q),1.25 (3H, t), 1.05 (3H, t); MS(ESI): 544 (MH⁺).

EXAMPLE 100 A. Preparation of4-Chloro-N-(2-dimethylaminoethyl)-3-nitrobenzamide

To a chilled solution (−10° C.) of 4-chloro-3-nitrobenzoyl chloride(0.92 g, 4.2 mmol) in anhydrous THF (20 mL) added dropwise a solution ofN,N-dimethylethylenediamine (0.44 mL, 4.0 mmol) in THF (20 mL). Afterstirring 30 min combined with a 1:1 mixture of ice and satd NaHCO₃ (50mL) and then extracted with EtOAc (3×80 mL). The combined organic layerswere dried (Na₂SO₄), concentrated and chromatographed (silica gel,MeOH/DCM, 3:22) to yield the title compound (0.40 g, 37%) as a paleyellow solid. ¹H-NMR (CDCl₃): δ 8.28 (1H, d), 7.96 (1H, dd), 7.63 (1H,d), 6.98 (1H, br s), 3.54 (2H, m), 2.56 (2H, t), 2.30 (6H, s).

B. Preparation of N-(2-Dimethylaminoethyl)-4-ethylamino-3-nitrobenzamide

To 2.0 M solution of ethylamine in THF (8 mL, 16 mmol) slowly added4-chloro-N-(2-dimethylaminoethyl)-3-nitrobenzamide (0.40 g, 1.5 mmol).After heating at 65° C. for 16 h, the reaction mixture was cooled,concentrated and chromatographed (silica gel, MeOH/DCM, 3:22) to affordthe title compound (0.30 g, 73%) as a yellow solid. ¹H-NMR (CD₃0D): δ8.75 (1H, d), 8.32 (1H, br s), 7.98 (1H, dd), 7.08 (1H, d), 3.58-3.64(3H, m), 3.43-3.51 (2H, m), 2.94 (2H, br t), 2.62 (6H, s), 1.35 (3H, t).

C. Preparation of3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-N-2-dimethylaminoethyl)-4-ethylaminobenzamide

In a manner similar to Example 30, intermediateN-(2-dimethylaminoethyl)-4-ethylamino-3-nitrobenzamide was hydrogenatedand then condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ7.44-7.54 (5H, m), 7.28-7.38 (4H, m), 7.18 (1H, m), 7.04 (1H, d), 6.89(1H, br s), 6.52 (1H, d), 5.19 (2H, s), 3.99 (1H, br t), 3.76 (3H, s),3.59 (2H, m), 3.02 (2H, m), 2.68 (2H, br s), 2.40 (6H, s), 1.03 (3H, t);MS(ESI): 587 (MH⁺).

EXAMPLE 101 A. Preparation of4-(4,5-Dihydrooxazol-2-yl)-N¹-ethylbenzene-1,2-diamine

To a chilled solution (−10° C.) of 4-chloro-3-nitrobenzoyl chloride(1.85 g, 8.4 mmol) in anhydrous THF (60 mL) was added dropwise asolution of ethanolamine (0.48 mL, 8.0 mmol) in THF (20 mL) followed byTEA (1.1 mL, 8.0 mmol). After stirring 1 h while temperature wasmaintained at −10° C., the solution was combined with a 1:1 mixture ofice and satd NaHCO₃ (100 mL) and then extracted with EtOAc (3×100 mL).The combined organic layers were washed with brine, dried (Na₂SO₄), andconcentrated to give 4-chloro-N-(2-hydroxyethyl)-3-nitrobenzamide (1.74g, 89%) as a white solid, which was used without purification. TLC (3:22MeOH/DCM R_(f) 0.36).

To a solution of intermediate4-chloro-N-(2-hydroxyethyl)-3-nitrobenzamide (0.40 g, 1.6 mmol) inanhydrous DCM (20 mL) added dropwise thionyl chloride (0.29 mL, 4.0mmol). After stirring 2 h the reaction mixture was diluted withchloroform and concentrated. The resulting yellow oil was dilutedcautiously with 2.0 M solution of ethylamine in THF (10 mL, 20 mmol) andheated in a sealed tube at 65° C. After 2 h the reaction mixture wascooled, concentrated and diluted with THF (20 mL). This solution wascombined with an aqueous solution of 20% KOH (5 mL) andtetrabutylammonium bromide (20 mg). After stirring rapidly 2 h themixture was extracted with Et₂O (2×100 mL). The combined organic layerswere washed with water and brine, dried (MgSO₄), concentrated andchromatographed (silica gel, MeOH/DCM, 1:19) to yield[4-(4,5-dihydrooxazol-2-yl)-2-nitrophenyl]ethylamine (0.17 g, 45%) as ayellow solid. TLC (1:19 MeOH/DCM R_(f) 0.56).

To a solution of this oxazoline intermediate (71 mg, 0.30 mmol) inethanol (2 mL) was added zinc dust (0.20 g) and HOAc (0.20 mL). Observedinitial exotherm and continued stirring 30 min. The reaction mixture wasdiluted with Et₂O (20 mL), filtered, combined cautiously with 15% NH₄OH(10 mL), and extracted again with Et₂O. The organic layers werecombined, washed with brine, dried (Na₂SO4), and concentrated underreduced pressure to yield the title compound (60 mg, 97%) as anoff-white solid, which was used without purification. ¹H-NMR (CDCl₃): δ7.45 (1H, dd), 7.35 (1H, d), 6.60 (1H, d), 4.38 (2H, t), 4.01 (2H, t),3.69 (1H, br s), 3.26 (2H, br s), 3.21 (2H, m), 1.32 (3H, t); TLC (1:19MeOH/DCM R^(f) 0.12).

B. Preparation of3-Benzyl-2-[5-(4,5-dihydrooxazol-2-yl)-2-ethylaminophenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to Example 1 byreplacing aniline with intermediate4-(4,5-dihydrooxazol-2-yl)-N¹-ethylbenzene-1,2-diamine. ¹H-NMR (CDCl₃):δ 7.64 (1H, d), 7.55 (1H, d), 7.52 (1H, d), 7.45-7.49 (2H, m), 7.27-7.37(4H, m), 7.18 (1H, m), 7.04 (1H, d), 6.55 (1H, d), 5.19 (2H, s), 4.38(2H, t), 4.02 (2H, t), 3.77 (3H, s), 3.04 (2H, m), 1.05 (3H, s);MS(ESI): 542 (MH⁺).

EXAMPLE 102 A. Preparation of 1-Methyl-2-methylthioquinoliniump-Toluenesulfonate

A mixture of 1-methylquinolin-2-thione (175 mg, 1.0 mmol) and methylp-toluenesulfonate (186 mg, 1.0 mmol) were heated at 130° C. After 30min the resulting solid was cooled, crushed, triturated with Et₂O (4×1mL) and dried under high vacuum to give the title compound (0.35 g, 97%)as a white solid. ¹H-NMR (DMSO-d₆): δ 8.96 (1H, d), 8.46 (1H, d), 8.35(1H, dd), 8.16 (1H, m), 8.08 (1H, d), 7.91 (1H, m), 7.47 (2H, d), 7.10(2H, d), 4.40 (3H, s), 3.02 (3H, s), 2.28 (3H, s).

B. Preparation of3-[3-Benzyl-5-(1-methyl-1H-quinolin-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

In a manner similar to Example 45, intermediate1-methyl-2-methylthioquinolinium p-toluenesulfonate was condensed with3-(3-benzyl-4-oxothiazolidin-2-ylideneamino)-4-ethylaminobenzonitrile toafford the title compound. ¹H-NMR (CDCl₃): δ 7.41-7.58 (4H, m),7.20-7.38 (9H, m), 6.49 (1H, d), 5.16 (2H, s), 3.79 (3, br s), 3.01 (2H,q), 1.02 (3H, t); MS(ESI): 492 (MH⁺).

EXAMPLE 103 Preparation of2-(5-Acetyl-2-ethylaminophenylimino)-3-benzyl-5-(1-methyl-1H-quinolin-2-ylidene)thiazolidin-4-one

In a manner similar to Example 102, 1-methyl-2-methylthioquinoliniump-toluenesulfonate was condensed with2-(5-acetyl-2-ethylaminophenylimino)-3-benzylthiazolidin-4-one to affordthe title compound. ¹H-NMR (CDCl₃): δ 7.66-7.71 (2H, m), 7.43-7.56 (4H,m), 7.20-7.38 (7H, m), 6.53 (1H, d), 5.20 (2H, s), 3.78 (3H, br s), 3.07(2H, q), 2.51 (3H, s), 1.06 (3H, t); MS(ESI): 509 (MH⁺).

EXAMPLE 104 Preparation of3-Benzyl-2-benzylimino-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with benzylamine. ¹H-NMR (CDCl₃): δ7.46-7.57 (3H, m), 7.22-7.37 (9H, m), 7.15 (1H, m), 7.03 (1H, br d),5.09 (2H, br s), 4.49 (2H, br s), 3.85 (3H, s); MS(ESI): 444 (MH⁺).

EXAMPLE 105 Preparation of2-(3-Acetylphenylimino)-3-furan-2-ylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 79 by replacing 3-picolyl isothiocyanate hydrobromide with2-furfuryl isothiocyanate. MS(ESI): 462 (MH⁺).

EXAMPLE 106 Preparation ofN-{4-[3-Furan-2-ylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}acetamide

The title compound was prepared in a manner similar to that described inExample 105 by replacing 3′-aminoacetophenone with 4′-aminoacetanilide.MS(ESI): 477 (MH⁺).

EXAMPLE 107 Preparation of[2-(5-Acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-yl]aceticAcid Methyl Ester

The title compound was prepared in a manner similar to Example 1 byreplacing 3-benzylrhodanine with rhodanine-3-acetic acid methyl ester.MS(ESI): 497 (MH⁺).

EXAMPLE 108 A. Preparation of 2-cyano-4-nitroacetanilide

The title compound was prepared in a manner similar to Example 80 byreplacing 2-amino-5-nitropyridine with 5-nitroanthranilonitrile. ¹H-NMR(CDCl₃): δ 8.78 (1H, d), 8.49 (1H, d), 8.44 (1H, dd), 7.88 (1H, br s),2.35 (3H, s).

B. Preparation ofN-{4-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-2-cyanophenyl}acetamide

In a manner similar to Example 30, intermediate2-cyano-4-nitroacetanilide was hydrogenated and then condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ 8.30(1H, d), 7.49-7.57 (4H, m), 7.27-7.38 (5H, m), 7.22 (1H, d), 7.19 (1H,m), 7.07 (1H, d), 5.14 (2H, s), 3.76 (3H, s), 2.27 (3H, s); MS(ESI): 512(MH⁺).

EXAMPLE 109 A. Preparation of 4′-Ethoxy-3′-nitroacetophenone

To a solution of 4′-hydroxy-3′-nitroacetophenone (1.0 g, 5.5 mmol) inanhydrous DMF (20 mL) was added anhydrous K₂CO₃ (3.0 g, 22 mmol) andthen bromoethane (0.49 mL, 6.6 mmol). After heating at 80° C. for 20 h,the reaction mixture was cooled, combined with satd aqueous NH₄Cl (50mL) and extracted with Et₂O (2×100 mL). The combined organic layers werewashed with water (3×50 mL), 1 N NaOH (50 mL) and then brine (50 mL),dried (Na₂SO₄) and concentrated under reduced pressure to afford thetitle compound (1.1 g, 96%) as a light brown solid, which was usedwithout further purification. ¹H-NMR (CDCl₃): δ 8.41 (1H, d), 8.15 (1H,dd), 7.14 (1H, d), 4.28 (2H, q), 2.61 (3H, s), 1.52 (3H, t).

B. Preparation of2-(5-Acetyl-2-ethoxyphenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

In a manner similar to Example 30, intermediate4′-ethoxy-3′-nitroacetophenone was hydrogenated and then condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ 7.77(1H, dd), 7.64-7.68 (2H, m), 7.61 (1H, d), 7.48 (1H, m), 7.25-7.36 (4H,m), 7.15 (1H, m), 6.99 (1H, d), 6.98 (1H, d), 5.20 (2H, s), 4.11 (2H,q), 3.69 (3H, s), 2.57 (3H, s), 1.43 (3H, t); MS(ESI): 516 (MH⁺).

EXAMPLE 110 Preparation of2-(5-Acetyl-2-hydroxyphenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

In a manner similar to Example 30, 4′-hydroxy-3′-nitroacetophenone washydrogenated and then condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. MS(ESI): 488 (MH⁺).

EXAMPLE 111 A. Preparation of3-Benzyl-1-methyl-2-thioxoimidazolidin-4-one

To a solution of sarcosine methyl ester hydrochloride (0.56 g, 4.0 mmol)and DBU (0.60 mL, 4.0 mmol) in anhydrous ethanol added benzylisothiocyanate (0.53 mL, 4.0 mmol). The resulting solution was heated atreflux 16 h, cooled, concentrated and chromatographed (silica gel, DCM)to give the title compound (0.88 g, quant.). ¹H-NMR (CDCl₃): δ 7.49-7.53(2H, m), 7.28-7.35 (3H, m), 5.02 (2H, s), 4.03 (2H, s), 3.34 (3H, s).

B. Preparation of3-Benzyl-1-methyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-thioxoimidazolidin-4-one

To a mixture of intermediate3-benzyl-1-methyl-2-thioxoimidazolidin-4-one (0.33 g, 1.5 mmol) and3-methyl-2-methylthiobenzothiazol-3-ium p-toluenesulfonate 0.66 g, 1.8mmol) in anhydrous MeCN (10 mL) added dropwise TEA (0.28 mL, 2.0 mmol).After 2 h the resulting product mixture was concentrated andchromatographed (silica gel, DCM) to afford the title compound (0.47 g,85%) as an orange-yellow solid. ¹H-NMR (CDCl₃): δ 7.54-7.61 (3H, m),7.46 (1H, m), 7.21-7.33 (5H, m), 5.19 (2H; s), 3.86 (3H, s), 3.77 (3H,s).

C. Preparation of2-(5-Acetyl-2-ethylaminophenylimino)-3-benzyl-1-methyl-5-(3-methyl-3H-benzothiazol-2-ylidene)imidazolidin-4-one

In a manner similar to Example 1, intermediate3-benzyl-1-methyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-thioxoimidazolidin-4-onewas alkylated with methyl p-toluenesulfonate and condensed with3′-amino-4′-ethylaminoacetophenone to yield the title compound. ¹H-NMR(CDCl₃): δ 8.11 (1H, d), 7.84 (1H, dd), 7.51 (1H, dd), 7.31 (1H, m),7.16 (1H, m), 6.95-7.12 (7H, m), 6.08 (1H, br t), 4.46 (2H, hs m), 3.99(2H, m), 3.78 (3H, s), 3.50 (3H, s), 2.65 (3H, s), 1.06 (3H, t);MS(ESI): 512 (MH⁺).

EXAMPLE 112 Preparation of4-Ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-3-(2-morpholin-4-ylethyl)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 83 by replacing 3-picolyl isothiocyanate hydrobromide withN-(2-ethylisothiocyanate)morpholine, synthesized fromN-(2-aminoethyl)morpholine and thiophosgene. ¹H-NMR (CDCl₃): δ 7.52 (1H,d), 7.32-7.37 (2H, m), 7.18-7.23 (2H, m), 7.09 (1H, d), 6.60 (1H, d),4.75 (1H, br s), 4.16 (1H, t), 3.81 (3H, s), 3.71 (4H, br s), 3.23 (2H,q), 2.76 (2H, br s), 2.60 (4H, br s), 1.29 (3H, t); MS(ESI): 521 (MH⁺).

EXAMPLE 113 Preparation of4-Ethylamino-3-[3-(4-methoxybenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 83 by replacing 3-picolyl isothiocyanate hydrobromide with4-methoxybenzylisothiocyanate. MS(ESI): 528 (MH⁺).

EXAMPLE 114 Preparation of4-Ethylamino-3-[3-(3-methoxybenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 83 by replacing 3-picolyl isothiocyanate hydrobromide with3-methoxybenzylisothiocyanate. ¹H-NMR (CDCl₃): δ 7.55 (1H, d), 7.37 (1H,t), 7.22-7.32 (4H, m), 7.12 (1H, d), 7.01 (2H, m), 6.86 (1H, d), 6.51(1H, d), 5.16 (2H, s), 4.32 (1H, t), 3.84 (3H, s), 3.81 (3H, s), 3.03(2H, q), 1.05 (3H, t); MS(ESI): 528 (MH⁺). Recrystallization of theproduct from hot MeCN afforded crystals suitable for single-crystalX-ray diffraction. Structural analysis showed that the E-isomer had beenobtained.

EXAMPLE 115 Preparation of4-Ethylamino-3-[3-(2-methoxybenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 83 by replacing 3-picolyl isothiocyanate hydrobromide with2-methoxybenzylisothiocyanate. MS(ESI): 528 (MH⁺).

EXAMPLE 116 A. Preparation of2-(3-Aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazoiidine-4-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing aniline with 1,3-phenylenediamine. MS(ESI): 445(MH⁺).

B. Preparation ofN-{3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}succinamicAcid

To a 25 mL flask was added2-(3-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one(100 mg, 225 μmol), anhydrous DCM (5 mL) and CHCl₃ (3 mL). To thesolution was added succinic anhydride (23 mg, 239 μmol). The reactionsolution was allowed to stir at 50° C. for 1.5 h. The white precipitateswere collected by filtration under reduced pressure, washed with DCM (10mL) and hexanes (20 mL), and then dried under vacuum to give the titlecompound (75 mg, 61%). MS(ESI): 545 (MH⁺).

EXAMPLE 117 Preparation ofN-{3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}benzenesulfonamide

To a 25 mL flask was added2-(3-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one(0.18 g, 0.40 mmol), anhydrous CHCl₃ (7 mL), benzenesulfonyl chloride(56 μL, 0.44 mmol), and TEA (0.10 mL, 0.80 mmol). The solution wasstirred at 50° C. for 20 h. The yellow precipitates were collected byfiltration under reduced pressure, washed with hexanes (30 mL), anddried under vacuum to give the title compound (49 mg, 21%) as a yellowsolid. ¹H-NMR (DMSO-d₆): δ 7.97 (1H, s), 7.76 (2H, d), 7.53 (2H, m),7.45 (2H, t), 7.37 (2H, d), 7.09-7.31 (8H, m), 6.81 (1H, d), 6.74 (1H,s), 6.57 (1H, d), 4.99 (2H, s), 3.72 (3H, s); MS(ESI): 585 (MH⁺).

EXAMPLE 118 Preparation of Thiophene-2-sulfonic Acid{3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}amide

The title compound was prepared in a manner similar to that described inExample 117 by replacing benzenesulfonyl chloride with2-(thiophene)sulfonyl chloride. MS(ESI): 591 (MH⁺).

EXAMPLE 119 Preparation ofN-{3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-3-methoxybenzamide

The title compound was prepared in a manner similar to that described inExample 117 by replacing benzenesulfonyl chloride with 3-methoxybenzoylchloride. MS(ESI): 579 (MH⁺).

EXAMPLE 120 Preparation ofN-{3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}methanesulfonamide

The title compound was prepared in a manner similar to that described inExample 117 by replacing benzenesulfonyl chloride with methanesulfonylchoride. ¹H-NMR (CDCl₃): δ 8.88 (1H, s), 7.48 (2H, d), 7.41 (1H, d),7.16-7.26 (5H, m), 7.09 (1H, t), 6.96 (2H, t), 6.89 (1H, m), 6.70 (1H,d), 5.05 (2H, s), 3.67 (3H, s), 2.92 (3H, s); MS(ESI): 532 (MH⁺).

EXAMPLE 121 Preparation of{3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}carbamicAcid Ethyl Ester

The title compound was prepared in a manner similar to the described inExample 117 by replacing benzenesulfonyl chloride with ethylchloroformate. MS(ESI): 517 (MH⁺).

EXAMPLE 122 Preparation of3-{3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-1,1-dimethylurea

The title compound was prepared in a manner similar to the described inExample 117 by replacing benzenesulfonyl chloride with dimethylcarbamylchloride. MS(ESI): 523 (MH⁺).

EXAMPLE 123 A. Preparation of Morpholin4-ylacetyl Chloride Hydrochloride

To a 100 mL flask was added morpholine (5.5 g, 63 mmol), benzene (20mL), and ethyl chloroacetate (3.2 mL, 30 mmol). The reaction solutionwas allowed to stir 1 h at ambient temperature. The resulting whitecrystalline solids were collected by filtration under reduced pressureand then transferred to a 100 mL flask along with dioxane (20 mL) and 1N NaOH (33 mL). The solution was allowed to stir at 80° C. for 16 h,cooled and then neutralized with 1N HCl. The aqueous solution was frozenand lyophilized to isolate the crude morpholinylacetic acid. The crudeacid (2.6 g, 20 mmol) and thionyl chloride (15 mL) was added to aN₂-purged 100 mL flask. After stirring 3 h the reaction solution wasfiltered and concentrated under reduced pressure to provide the titlecompound (3.1 g, 78%) as a white powder. ¹H-NMR (DMSO-d₆): δ 7.58 (1H,s), 3.48 (2H, s), 3.37 (4H, m), 2.76 (4H, m); ¹³C-NMR (DMSO-d₆): δ166.0, 63.5, 55.5, 51.8.

B. Preparation ofN-{3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-morpholin-4-ylacetamide

The title compound was prepared in a manner similar to that described inExample 117 by replacing benzenesulfonyl chloride withmorpholin-4-ylacetyl chloride hydrochloride. ¹H-NMR (CDCl₃): δ 8.98 (1H,s), 7.51 (2H, d), 7.41 (1H, d), 7.34 (1H, d), 7.19-7.27 (5H, m), 7.08(2H, m), 6.91 (1H, d), 6.70 (1H, d), 5.06 (2H, s), 3.70 (4H, t), 3.63(3H, s), 3.07 (2H, s), 2.55 (4H, t); MS(ESI): 572 (MH⁺).

EXAMPLE 124 Preparation ofN-{4-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-morpholin-4-ylacetamide

The title compound was prepared from the product of Example 4 in amanner similar to that described in Example 123. MS(ESI): 572 (MH⁺).

EXAMPLE 125 Preparation ofN-{3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-dimethylaminoacetamide

To a 25 mL flask was added N,N-dimethylglycine (500 mg, 4.85 mmol) andthionyl chloride (5 mL). The resulting solution was allowed to stir atambient temperature under N₂ for 3 h. The excess thionyl chloride wasremoved in vacuo to provide N,N-dimethylaminoacetyl chloridehydrochloride as a white powder.

To a solution of2-(3-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one(160 mg, 360 μmol) in chloroform (8 mL) was addedN,N-dimethylaminoacetyl chloride hydrochloride (90 mg, 0.58 mmol) andTEA (150 μL, 1.1 mmol). The reaction solution was heated at reflux for20 h, cooled, and concentrated in vacuo. The crude material waschromatographed (silica gel, 0-50% EtOAc/Hex) to give the title compound(34 mg, 18%) as a yellow solid. ¹H-NMR (CDCl₃): δ 9.03 (1H, s), 7.50(2H, d), 7.37 (2H, t), 7.17-7.26 (5H, m), 7.11 (1H, m), 7.05 (1H, t),6.88 (1H, d), 6.68 (1H, d), 5.03 (2H), 3.60 (3H, s), 3.00 (2H, s), 2.28(6H, s); MS(ESI): 530 (MH⁺).

EXAMPLE 126 Preparation of{4-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}carbamicAcid Ethyl Ester

The title compound was prepared from the product of Example 4 in amanner similar to that described in Example 121. ¹H-NMR (CDCl₃): δ 7.49(2H, d), 7.37 (1H, d), 7.20-7.29 (5H, m), 7.07 (1H, t), 6.87-6.95 (3H,m), 6.54 (1H, br s), 5.07 (2H, s), 4.15 (2H, q), 3.61 (3H, s), 1.24 (3H,t); MS(ESI): 517 (MH⁺).

EXAMPLE 127 Preparation ofN-{4-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-dimethylaminoacetamide

The title compound was prepared from the product of Example 4 in amanner similar to that described in Example 125. MS(ESI) 530 (MH⁺).

EXAMPLE 128 Preparation ofN-{4-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}methanesulfonamide

The title compound was prepared from the product of Example 4 in amanner similar to that described in Example 120. MS(ESI): 523 (MH⁺).

EXAMPLE 129 Preparation of4-Ethylamino-3-[3-(3-hydroxybenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

To a N₂-purged flask was added the product of Example 114 (60 mg, 0.11mmol) and anhydrous DCM (5 mL). The solution was cooled to −78° C. priorto the addition of a 1.0M solution of BBr₃ in DCM (0.50 mL). Thesolution was allowed to warm to ambient temperature with stirring. After7 h the solution was quenched by addition of MeOH (10 mL) and thenconcentrated under reduced pressure. The crude material was purified byreverse-phase HPLC (C18 column), eluting with 0.05% TFA in MeCN—H₂O (1:9to 9:1) to provide the title compound (15 mg, 26%). ¹H-NMR (CDCl₃): δ7.40 (1H, d), 7.35 (1H, t), 7.29 (1H, dd), 7.13-7.25 (3H, m), 6.95-7.01(3H, m), 6.76 (1H, dd), 6.49 (1H, d), 5.08 (2H, s), 3.56 (3H, s), 3.02(2H, q), 1.05 (3H, t); MS(ESI): 514 (MH⁺).

EXAMPLE 130 Preparation of 4′-Ethylamino-3′-nitroacetanilide

To a solution of 4-fluoro-3-nitroaniline (2.5 g, 16 mmol) in DCM (35 mL)was added acetic anhydride (2.3 mL, 24 mmol). The solution was stirred15 min, and the resulting off-white precipitates were collected byfiltration under reduced pressure. To a solution of the intermediateacetanilide in anhydrous THF (15 mL) was added a 2.0M solution ofethylamine in THF (8.0 mL). The solution was stirred at ambienttemperature 14 h, and the resulting precipitates were collected byfiltration under reduced pressure and dried under vacuum to provide thetitle compound (2.4 g, 68%). ¹H-NMR (CDCl₃): δ 8.08 (1H, d), 7.90 (1H,br s), 7.78 (1H, dd), 7.32 (1H, br s), 6.82 (1H, d), 3.35 (2H, q), 2.16(3H, s), 1.36 (3H, t).

B. Preparation of4-Ethylamino-3-[3-(3-fluorobenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

In a manner similar to Example 30, intermediate4′-ethylamino-3′-nitroacetanilide was hydrogenated and then condensedwith3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ 9.58(1H, s), 7.76 (1H, d), 7.18-7.46 (9H, m), 7.12 (1H, d), 6.47 (1H, d),5.09 (2H, s), 3.82 (1H, br s), 3.79 (3H, s), 2.92 (2H, t), 1.98 (3H, s),0.97 (3H, t); MS(ESI): 530 (MH⁺).

EXAMPLE 131 Preparation of4-Ethylamino-3-[3-(3-fluorobenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was synthesized in a manner similar or to thatdescribed in Example 83 by replacing 3-picolyl isothiocyanatehydrobromide with 3-fluorobenzylisothiocyanate. MS(ESI): 516 (MH⁺).

EXAMPLE 132 Preparation of4-Ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-(3-trifluoromethylbenzyl)thiazolidin-2-ylideneamino]benzonitrile

The title compound was synthesized in a manner similar to that describedin Example 83 by replacing 3-picolyl isothiocyanate hydrobromide with3-(trifluoromethyl)benzylisothiocyanate. MS(ESI): 566 (MH⁺).

EXAMPLE 133 Preparation of4-Ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-(2-trifluoromethylbenzyl)thiazolidin-2-ylideneamino]benzonitrile

The title compound was synthesized in a manner similar to that describedin Example 83 by replacing 3-picolyl isothiocyanate hydrobromide with2-(trifluoromethyl)benzylisothiocyanate. MS(ESI): 566 (MH⁺).

EXAMPLE 134 Preparation of4-Ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-3-(3-methylbenzyl)-4-oxothiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 83 by replacing 3-picolyl isothiocyanate hydrobromide with3-methylbenzylisothiocyanate. MS(ESI): 512 (MH⁺).

EXAMPLE 135 A. Preparation of4′-Ethylamino-2-(morpholin-4-yl)-3′-nitroacetanilide

The title compound was synthesized in a manner similar to Example 130 byreplacing acetic anhydride with morpholin-4-ylacetyl chloridehydrochloride. ¹H-NMR (CDCl₃): δ 8.94 (1H, s), 8.11 (1H, d), 7.88 (1H,dd), 6.83 (1H, d), 3.78 (4H, t), 3.34 (2H, q), 3.13 (2H, s), 2.62 (4H,t), 1.31 (3H, t).

B. Preparation ofN-{3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-morpholin-4-ylacetamide

In a manner similar to Example 30, intermediate4′-ethylamino-2-(morpholin-4-yl)-3′-nitroacetanilide was hydrogenatedand then condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ 8.87(1H, s), 7.49-7.53 (3H, m), 7.28-7.37 (5H, m), 7.19 (1H, t), 7.12 (1H,dd), 7.04 (1H, d), 6.57 (1H, d), 5.19 (2H, s), 3.79 (8H, br s), 3.16(2H, s), 3.01 (2H, q), 2.66 (4H, br s), 1.06 (3H, t); MS(ESI): 615(MH⁺).

EXAMPLE 136 Preparation of3-[3-(3-Chlorobenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was synthesized in a manner similar to that describedin Example 83 by replacing 3-picolyl isothiocyanate hydrobromide with3-chlorobenzylisothiocyanate. MS(ESI): 533 (MH⁺).

EXAMPLE 137 Preparation of3-[3-(3-Bromobenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was synthesized in a manner similar to that describedin Example 83 by replacing 3-picolyl isothiocyanate hydrobromide with3-bromobenzylisothiocyanate. MS(ESI): 578 (MH⁺).

EXAMPLE 138 A. Preparation of4′-Ethylamino-3′-nitro-2,2,2-trifluoroacetanilide

The title compound was prepared in a manner similar to that described inExample 130 by replacing acetic anhydride with trifluoroacetic anhydride(TFAA). TLC (1:1 Hex/EtOAc) R_(f)=0.5; MS(ESI): 278 (MH⁺).

B. Preparation ofN-{3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2,2,2-trifluoroacetamide

In a manner similar to Example 30, intermediate4′-ethylamino-3′-nitro-2,2,2-trifluoroacetanilide was hydrogenated andthen condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. MS(ESI): 584 (MH⁺).

EXAMPLE 139 A. Preparation of2-Dimethylamino-4′-ethylamino-3′-nitroacetanilide

The title compound was prepared in a similar manner as that described inExample 130 by replacing acetic anhydride with N,N-dimethylaminoacetylchloride hydrochloride. ¹H-NMR (CDCl₃): δ 9.04 (1H, s), 8.16 (1H, d),7.95 (1H, dd), 7.89 (1H, br s), 6.84 (1H, d), 3.35.(2H,.q), 3.09 (2H,s), 2.39 (6H, s), 1.36 (3H, t); MS(ESI): 267 (MH⁺).

B. Preparation ofN-{3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-dimethylaminoacetamide

In a manner similar to Example 30, intermediate2-dimethylamino-4′-ethylamino-3′-nitroacetanilide was hydrogenated andthen condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ 8.85(1H, s), 7.43 (3H, t), 7.18-7.28 (5H, m), 7.10 (2H, t), 6.95 (1H, d),6.48 (1H, d), 5.10 (2H, s), 3.71 (3H, s), 3.03 (2H, s), 2.93 (2H, q),2.33 (6H, s), 0.97 (3H, t); MS(ESI): 584(MH⁺).

EXAMPLE 140 A. Preparation of 4-Ethylamino-3-nitroaniline

To a pressure tube was added 4-fluoro-3-nitroaniline (550 mg, 3.50 mmol)and a 2.0 M solution of ethylamine in THF (8 mL). The sealed tube washeated at 120° C. for 24 h. The reaction solution was cooled, dilutedwith EtOAc (30 mL), washed with satd NaHCO₃ (2×25 mL), dried overNa₂SO₄, and concentrated under reduced pressure to provide the titlecompound (625 mg, 98%) as a purple solid. ¹H-NMR (CDCl₃): δ 7.72 (1H, brs), 7.49 (1H, d), 6.96 (1H, dd), 6.74 (1H, d), 3.45 (2H, br s), 3.30(2H, m), 1.33 (3H, t).

B. Preparation of 4-Methylpiperazine-1-carboxylic Acid(4-Ethylamino-3-nitro-phenyl)amide

To a 100 mL flask was added 4-ethylamino-3-nitroaniline (625 mg, 3.45mmol), chloroform (30 mL), and triphosgene (341 mg, 1.15 mmol). To thesolution was added satd NaHCO₃ (30 mL), and the biphasic mixture wasstirred for 30 min. The organic phase was partitioned, dried overNa₂SO₄, filtered, and concentrated under reduced pressure. The residuewas dissolved in anhydrous THF (16 mL), and 4-methylpiperizine (291 mg,2.90 mmol) was added. The solution was stirred at 40° C. for 1 h, cooledand concentrated under reduced pressure to provide the title compound(1.0 g, 94%) as a red solid. ¹H-NMR (CDCl₃): δ 7.91 (1H, d), 7.84 (1H,t), 7.61 (1H, dd), 6.95 (1H, s), 6.73 (1H, d) 3.52 (4H, t), 3.31 (2H,m), 2.42 (4H, t), 2.32 (3H, s), 1.34 (3H, t); MS(ESI): 308 (MH⁺).

C. Preparation of 4-Methylpiperazine-1-carboxylic Acid{3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}amide

In a manner similar to Example 30, intermediate4-methylpiperazine-1-carboxylic acid (4-ethylamino-3-nitro-phenyl)amidewas hydrogenated and then condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. MS(ESI): 614 (MH⁺).

EXAMPLE 141 Preparation of2-(5-Amino-2-ethylaminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

To the product of Example 138 (0.15 g, 0.26 mmol) in MeOH (30 mL) wasadded H₂O (6 mL) and fine mesh K₂CO₃ (0.30 g, 1.5 mmol), and thesolution was stirred 24 h at 55° C. The reaction mixture was cooled,diluted with EtOAc (30 mL), washed with H₂O (20 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The crude materialwas purified by reverse-phase HPLC (C18 column), eluting with 0.05% TFAin MeCN—H₂O (1:9 to 9:1) to provide the title compound (2 mg). MS(ESI):488 (MH⁺).

EXAMPLE 142 A. Preparation of4′-Ethylamino-2-(4-methylpiperazin-1-yl)-3′-nitroacetanilide

To a 100 mL flask was added 4-fluoro-3-nitroaniline (0.83 g, 5.3 mmol),DCM (30 mL), bromoacetyl chloride (0.53 mL, 6.4 mmol), and TEA (0.74 mL,5.3 mmol). The reaction solution was stirred at room temperature 2 h andthen quenched with satd NaHCO₃ (20 mL). The organic phase waspartitioned, dried over Na₂SO₄, filtered under vacuum, and concentratedunder reduced pressure. The resulting amide (1.31 g, 4.73 mmol) wasadded to a 100 mL flask along with MeCN (20 mL), 4-methylpiperizine(0.53 mL, 4.7 mmol), and K₂CO₃ (655 mg, 4.74 mmol). The reaction slurrywas stirred 14 h at 35° C. prior to removal of excess K₂CO₃ by vacuumfiltration. The filtrate was concentrated under reduced pressure, andthe crude residue was chromatographed (SiO₂, hexane/EtOAc) to provide400 mg of intermediate amide. In a manner similar to that described inExample 31, the intermediate amide was treated with ethylamine to affordthe title compound. ¹H-NMR (CDCl₃): δ 9.66 (1H, s), 8.44 (1H, m), 8.05(1H, m), 7.17 (1H, t), 3.25 (2H, s), 3.19 (4H, m), 3.14 (2H, m), 2.88(4H, m), 2.53 (3H, 2), 1.38 (3H, t); MS(ESI): 322 (MH⁺).

B. Preparation ofN-{3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-(4-methylpiperazin-1-yl)acetamide

In a manner similar to Example 30, intermediate4′-ethylamino-2-(4-methylpiperazin-1-yl)-3′-nitroacetanilide washydrogenated and then condensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluene sulfonate to afford the title compound. MS(ESI): 628 (MH⁺).

EXAMPLE 143 Preparation ofN-{3-[3-Benzyl-5-(5-methoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-dimethylaminoacetamide

The title compound was prepared in a manner similar to Example 1 byreplacing 2-(methylthio)benzothiazole with2-mercapto-5-methoxybenzothiazole and by replacing aniline with3′-amino-2-dimethylamino-4′-ethylaminoacetanilide. MS(ESI): 603 (MH⁺).

EXAMPLE 144 Preparation ofN-{3-[3-Benzyl-5-(5-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-dimethylaminoacetamide

The title compound was prepared from the product of Example 143 in amanner similar to that described in Example 129. MS(ESI): 589 (MH⁺).

EXAMPLE 145 A. Preparation of5-(2-Chloroethoxy)-2-methylthio-benzothiazole

To a 250 mL flask was added 2-mercapto-5-methoxybenzothiazole (5.1 g, 26mmol), MeCN (63 mL), methyl p-toluenesulfonate (4.8 g, 26 mmol) and TEA(4.4 mL, 31 mmol). After stirring 16 h at ambient temperature, thesolution was concentrated under reduced pressure. The crude material wasdiluted with EtOAc (200 mL), washed with water (2×75 mL), dried overNa₂SO₄, filtered, and concentrated. The resulting viscous oil wasdissolved in DCM (40 mL), and transferred to an argon-purged 250 mLflask. The solution was cooled to −78° C. prior to the addition of a 1.0M BBr₃ solution in DCM (64 mL). The reaction suspension was allowed towarm to room temperature. After 16 h the reaction solution was cooled to−78° C. and quenched by addition of MeOH (100 mL). The resultingprecipitates were isolated by vacuum filtration to yield5-hydroxy-2-methylthio-benzothiazole (3.9 g, 76%) as a white solid.

To a solution of 5-hydroxy-2-methylthio-benzothiazole (2.1 g, 11 mmol)in anhydrous DMF (25 mL) was added bromo-2-chloroethane (4.4 mL, 53mmol) and powdered K₂CO₃ (7.3 g, 53 mmol). The reaction slurry washeated at 70° C. for 13 h. The slurry was filtered under vacuum and thefiltrate was concentrated under reduced pressure. The crude material waschromatographed (SiO₂, 0-20% EtOAc/Hex) to afford the title compound(1.2 g, 46%). ¹H-NMR (CDCl₃): δ 7.62 (1H, d), 7.39 (1H, d), 6.97 (1H,dd), 4.29 (2H, t), 3.85 (2H, t), 2.79 (3H, s); MS(ESI): 259 (MH⁺).

B. Preparation of3-Benzyl-5-[5-(2-chloroethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazoliump-Toluenesulfonate

The title compound was prepared in a manner similar to that described inExample 1 by replacing 2-(methylthio)benzothiazole with5-(2-chloroethoxy)-2-methylthio-benzothiazole. ¹H-NMR (DMSO-d₆): δ 8.08(1H, d), 7.65 (1H, d), 7.36-7.53 (7H, m), 7.22 (1H, dd), 7.09 (1H, d),5.38 (2H, s), 4.45 (2H, t), 4.25 (3H, s), 4.03 (2H, t), 3.01 (3H, s),2.28 (3H, s) MS(ESI): 463 (M⁺−p-toluenesulfonate).

C. Preparation ofN-(3-{3-Benzyl-5-[5-(2-chloroethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylaminoacetamide

In a manner similar to Example 30, intermediate2-dimethylamino-4′-ethylamino-3′-nitroacetanilide was hydrogenated andthen condensed with3-benzyl-5-[5-(2-chloroethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. MS(ESI): 651 (MH⁺).

EXAMPLE 146 A. Preparation of3-Benzyl-5-[5-(2-methoxyethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazoliump-Toluenesulfonate

The title compound was synthesized in a manner similar to that describedin Example 145 by replacing bromo-2-chloroethane with 2-chloroethylmethylether. MS(ESI): 459 (M⁺−p-toluenesulfonate).

B. Preparation ofN-(3-{3-Benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylaminoacetamide

In a manner similar to Example 30, intermediate2-dimethylamino-4′-ethylamino-3′-nitroacetanilide was hydrogenated andthen condensed with3-benzyl-5-[5-(2-methoxyethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-hiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ 9.08(11H, s), 7.46 (2H, d), 7.27-7.35 (5H, m), 7.16 (1H, dd), 6.69 (1H, dd),6.62 (1H, d), 6.51 (1H, d), 5.14 (2H, s), 4.13 (2H, t), 3.75 (2H, t),3.71 (2H, s), 3.44 (3H, s), 3.19 (2H, s), 2.94 (2H, q), 2.46 (6H, s),1.02 (3H, t); MS(ESI): 647 (MH⁺).

EXAMPLE 147 A. Preparation of4′-Ethylamino-2-methoxy-3′-nitroacetanilide

The title compound was prepared in a similar manner as that described inExample 130 by replacing acetic anhydride with methoxyacetyl chloride.¹H-NMR (CDCl₃): δ 8.20 (1H, d), 8.17 (1H, br s), 7.88 (1H, dd), 6.68(1H, d), 4.03 (2H, s), 3.52 (3H, s), 3.37 (2H, q), 1.62 (2H, br s), 1.38(3H, t).

B. Preparation ofN-{3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-methoxyacetamide

In a manner similar to Example 30, intermediate4′-ethylamino-2-methoxy-3′-nitroacetanilide was hydrogenated and thencondensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ 7.99(1H, s), 7.39-7.44 (3H, m), 7.17-7.28 (5H, m), 7.05-7.11 (2H, m), 694(1H, d), 6.50 (1H, d), 5.08 (2H, s), 3.92 (2H, s), 3.66 (3H, s), 3.41(3H, s), 2.91 (2H, q), 0.96 (3H, t); MS(ESI): 560 (MH⁺).

EXAMPLE 148 Preparation ofN-(3-{3-Benzyl-5-[5-(2-dimethylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylaminoacetamide

To a pressure tube was added the product of Example 145 (150 mg, 0.23mmol), tetra-n-butylammonium iodide (85 mg, 0.23 mmol), and 2.0 Msolution of dimethylamine in THF (6 mL). The tube was sealed and heatedat 65° C. for 14 h. The solution was cooled and concentrated underreduced pressure, and the crude material was purified by chromatography(silica gel, 0-20% MeOH/DCM) to provide the title compound (30 mg, 20%).¹H-NMR (CDCl₃): δ 8.83 (1H, s), 7.45 (2H, d), 7.22-7.34 (5H, m), 7.11(1H, dd), 6.71 (1H, dd), 6.63 (1H, d), 6.52 (1H, d), 5.14 (2H, s), 4.12(2H, t), 3.70 (3H, s), 3.04 (2H, s), 2.97 (2H, q), 2.82 (2H, t), 2.40(6H, s), 2.35 (6H, s), 1.02 (3H, t); MS(ESI): 660 (MH⁺).

EXAMPLE 149 Preparation ofN-(3-{3-Benzyl-5-[5-(2-hydroxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylamino-acetamide

To an 8 mL vial was added the product of Example 145 (100 mg, 0.15mmol), anhydrous DMF (5 mL), and tetra-n-butylammonium iodide (570 mg,1.54 mmol). The solution was heated at 75° C. for 4 h prior to theaddition of sodium acetate (250 mg, 3.08 mmol). The reaction solutionwas then heated 16 h at 75° C. To the solution was added MeOH (2 mL), 5Maqueous NaOH (1 mL) and H₂O (1 mL). After heating at 50° C. for 5 h, thereaction mixture was cooled, neutralized with conc HCl and concentratedunder reduced pressure. The residue was taken up into DCM (50 mL), andthe organic phase was washed with water (2×25 mL), dried over Na₂SO₄,filtered, and concentrated under reduced pressure. The crude materialwas chromatographed (SiO₂, 0-10% MeOH/DCM) to provide the title compound(5 mg, 5%). ¹H NMR (MeOH-d₄): δ 8.92 (1H, s), 7.11-7.26 (7H, m), 6.97(1H, dd), 6.66 (1H, dd), 6.60 (1H, d), 6.44 (1H, d), 5.01 (2H, s), 3.96(2H, t), 3.77 (2H, t), 3.62 (3H, s), 3.00 (2H, s), 2.82 (2H, q), 2.28(6H, s), 0.89 (3H, t); MS(ESI) 633 (MH⁺).

EXAMPLE 150 A. Preparation of2-(5-Acetyl-2-ethylaminophenylimino)-3-furan-2-ylmethyl-thiazolidin-4-one

The title compound was prepared from furfuryl isothiocyanate and3′-amino-4′-(ethylamino)acetophenone in a manner similar to thatdescribed in Example 52. ¹H-NMR (CDCl₃): δ 7.73 (1H, dd), 7.61 (1H, s),7.38 (1H, s), 6.59 (1H, d), 6.43 (1H, d), 6.36 (1H, m), 5.06 (2H, s),3.88 (2H, s), 3.21 (2H, q), 2.50 (3H, s), 1.27 (3H, t); MS(ESI): 358(MH⁺).

B. Preparation of2-(5-Acetyl-2-ethylaminophenylimino)-5-[5-(2-chloroethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-furan-2-ylmethylthiazolidin-4-one

In a manner similar to Example 45, intermediate5-(2-chloroethoxy)-2-(methylthio)benzothiazole was alkylated withmenthyl p-toluenesulfonate and then condensed with the above2-(5-acetyl-2-ethylaminophenylimino)-3-furan-2-ylmethyl-thiazolidin-4-one.MS(ESI): 583 (MH⁺).

EXAMPLE 151 Preparation of2-(5-Acetyl-2-ethylaminophenylimino)-3-furan-2-ylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was synthesized in a manner similar to that describedin Example 82 by replacing 3-picolyl isothiocyanate hydrobromide with2-furfuryl isothiocyanate. ¹H-NMR (CDCl₃): δ 7.70-7.74 (2H, m), 7.52(1H, d), 7.33-7.39 (2H, m), 7.20 (1H, t), 7.06 (1H, d), 6.68 (1H, d),6.50 (1H, d), 6.35 (1H, m), 5.24 (2H, s), 3.76 (3H, s), 3.23 (2H, q),2.49 (3H, s), 1.28 (3H, t); MS(ESI): 505 (MH⁺).

EXAMPLE 152 Preparation ofN-(3-{3-Benzyl-5-[5-(2-chloroethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-methoxyacetamide

In a manner similar to Example 30, intermediate4′-ethylamino-2-methoxy-3′-nitroacetanilide was hydrogenated and thencondensed with 3-benzyl-5-[5-(2-chloroethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. MS(ESI): 638 (M H+).

EXAMPLE 153 Preparation ofN-{4-Ethylamino-3-[3-furan-2-ylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-methoxyacetamide

The title compound was prepared in a manner similar to that described inExample 84 by replacing 3-amino-4-(ethylamino)benzonitrile with3′-amino-4′-ethylamino-2-methoxyacetanilide. ¹H-NMR (CDCl₃): δ 8.07 (1H,s), 7.50 (1H, dd), 7.37 (1H, d), 7.29-7.34 (2H, m), 7.16 (2H, m), 7.02(1H, d), 6.66 (1H, br s), 6.45 (1H, d), 6.32 (1H, m), 5.15 (2H, s), 3.99(2H, s), 3.75 (3H, s), 3.51 (3H, s), 3.13 (2H, q), 1.23 (3H, t);MS(ESI): 550 (MH⁺).

EXAMPLE 154 Preparation ofN-(3-{3-Benzyl-5-[5-(2-dimethylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-methoxyacetamide

The title compound was prepared from the product of Example 152 in amanner similar to that described in Example 148. ¹H-NMR (CDCl₃): δ 8.03(1H, s), 7.48 (2H, d), 7.24-7.37 (5H, m), 7.14 (1H, dd), 6.74 (1H, dd),6.65 (1H, d), 6.53 (1H, d), 5.16 (2H, s), 4.13 (2H, t), 4.00 (2H, s),3.72 (3H, s), 3.48 (3H, s), 2.99 (2H, q), 2.81 (2H, t), 2.39 (6H, s),1.03 (3H, t); MS(ESI): 647 (MH⁺).

EXAMPLE 155 Preparation of2-(5-Acetyl-2-ethylaminophenylimino)-5-[5-(2-dimethylamino-ethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-furan-2-ylmethylthiazolidin-4-one

The title compound was prepared from the product of Example 150 in amanner similar to that described in Example 148. ¹H-NMR (CDCl₃): δ7.67-7.72 (2H, m), 7.37 (1H, s), 7.35 (1H, d), 6.76 (1H, dd), 6.64 (1H,d), 6.57 (1H, d), 6.45 (1H, d), 6.34 (1H, dd), 5.18 (2H, s), 4.89 (1H,t), 4.10 (2H, t), 3.71 (3H, s), 3.22 (2H, m), 2.75 (2H, m), 2.51 (3H,s), 2.35 (6H, s), 0.97 (3H, t); MS(ESI): 592 (MH⁺).

EXAMPLE 156 A. Preparation ofN-[4-Ethylamino-3-(3-furan-2-ylmethyl-4-oxothiazolidin-2-ylideneamino)phenyl]-2-methoxyacetamide

The title compound was synthesized from 2-furfuryl isothiocyanate and3′-amino-4′-ethylamino-2-methoxyacetanilide in a manner similar to thatdescribed in Example 52. MS(ESI): 403 (MH⁺).

B. Preparation ofN-(3-{5-[5-(2-Dimethylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-furan-2-ylmethyl-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-methoxyacetamide

In a manner similar to Example 45, intermediate5-(2-chloroethoxy)-2-(methylthio)benzothiazole was alkylated with methylp-toluenesulfonate and then condensed with the aboveN-[4-ethylamino-3-(3-furan-2-ylmethyl-4-oxothiazolidin-2-ylideneamino)phenyl]-2-methoxyacetamide.The resulting product was transformed into the title compound followingthe procedure outlined in Example 148. MS(ESI): 583 (MH⁺).

EXAMPLE 157 A. Preparation of2-Acetoxy-4′-ethylamino-3′-nitroacetanilide

To a 100 mL flask was added 4-ethylamino-3-nitroaniline (1.1 g, 6.3mmol) and anhydrous CHCl₃ (45 mL). The solution was cooled to 0° C.prior to the addition of bromoacetyl chloride (0.62 mL, 7.5 mmol) andTEA (1.7 mL, 13 mmol) under a nitrogen atmosphere. The reaction mixturewas allowed to warm to ambient temperature over 1 h before the solventwas removed under reduced pressure. The crude material waschromatographed (SiO₂, 0-40% EtOAc/Hex) to provide the intermediateacetanilide (540 mg, 1.8 mmol) as a red solid. To a solution of theintermediate in anhydrous DMF (25 mL) was added sodium acetate (1.41 g,17.2 mmol). The suspension was heated at 100° C. for 4 h. After cooling,the reaction mixture was diluted with EtOAc (25 mL), and the excesssodium acetate was removed by filtration under reduced pressure. Thefiltrate was concentrated under reduced pressure to provide the titlecompound (420 mg). ¹H-NMR (CDCl₃): δ 8.13 (1H, br s), 8.11 (1H, d), 7.90(1H, br s), 7.79 (1H, dd), 6.80 (1H, d), 4.68 (2H, s), 3.33 (2H, m),2.21 (3H, s), 1.35 (3H, t); MS(ESI): 282 (MH⁺).

B. Preparation of Acetic Acid{3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenylcarbamoyl}methylEster

In a manner similar to Example 30, intermediate2-acetoxy-4′-ethylamino-3′-nitroacetanilide was hydrogenated and thencondensed with3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford the title compound. ¹H-NMR (CDCl₃): δ 7.73(1H, br s), 7.44-7.51 (3H, m), 7.23-7.34 (5H, m), 7.16 (1H, t), 7.08(1H, dd), 7.00 (1H, d), 6.56 (1H, d), 5.15 (2H, s), 4.67 (2H, s), 3.74(3H, s), 2.98 (2H, q), 2.20 (3H, s), 1.00 (3H, t); MS(ESI): 588 (MH⁺).

EXAMPLE 158 Preparation ofN-{3-[3-Benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-hydroxyacetamide

To a 50 mL flask was added the product of Example 157 (0.19 g, 0.32mmol), CHCl₃ (5 mL), MeOH (10 mL), water (2 mL), and potassium carbonate(0.22 g, 1.6 mmol). After 4 h the reaction mixture was diluted withCHCl₃ (40 mL), and the organic phase was partitioned, washed with water(20 mL), dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The crude sample was chromatographed (silica gel, 0-10%MeOH/DCM) to afford the title compound (37 mg, 21%). ¹H-NMR (CDCl₃): δ8.14 (1H, s), 7.42-7.48 (3H, m), 7.27-7.33 (5H, m), 7.15 (1H, t), 7.09(1H, dd), 6.99 (1H, d), 6.56 (1H, d), 5.15 (2H, s), 4.14 (2H, s), 3.71(3H, s), 2.95 (2H, q), 0.99 (3H, t); MS(ESI): 546 (MH⁺).

EXAMPLE 159 Preparation ofN-(3-{3-Benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-hydroxyacetamide

In a manner similar to Example 30, intermediate2-acetoxy-4′-ethylamino-3′-nitroacetanilide was hydrogenated and thencondensed with3-benzyl-5-[5-(2-methoxyethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate to afford an intermediate thiazolidinone, which washydrolyzed in a manner similar to Example 158 to provide the titlecompound. MS(ESI): 620 (MH⁺).

EXAMPLE 160 Preparation of2-(3-Acetylphenylimino)-3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]thiazolidin-4-one

The title compound was synthesized in a manner similar to that describedin Example 146 by condensing 3′-aminoacetophenone with3-benzyl-5-[5-(2-methoxyethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate. ¹H-NMR (CDCl₃): δ 7.75 (1H, d), 7.60-7.64 (3H, m),7.28-7.50 (6H, m), 7.24 (1H, d), 6.85 (1H, m), 5.21 (2H, s), 4.18 (2H,m), 3.80 (2H, m), 3.70 (3H, s), 3.48 (3H, s), 2.65 (3H, s); MS(ESI): 546(MH⁺).

EXAMPLE 161 Preparation of2-(5-Acetyl-2-ethylaminophenylimino)-3-furan-2-ylmethyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 150 by replacing 5-(2-chloroethoxy)-2-(methylthio)benzothiazolewith 5-(2-methoxyethoxy)-2-(methylthio)benzothiazole. ¹H-NMR (CDCl₃): δ7.69 (1H, dd), 7.66 (1H, d), 7.34-7.37 (2H, m), 6.76 (1H, dd), 6.65 (1H,d), 6.59 (1H, d), 6.45 (1H, d), 6.33 (1H, m), 5.18 (2H, s), 4.14 (2H,m), 3.75 (2H, m), 3.70 (3H, s), 3.44 (3H, s), 3.20 (2H, q), 2.51 (3H,s), 1.26 (3H, t); MS(ESI): 579 (MH⁺).

EXAMPLE 162 Preparation ofN-(4-Ethylamino-3-{3-furan-2-ylmethyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}phenyl)-2-methoxyacetamide

In a manner similar to Example 156,5-(2-methoxyethoxy)-2-(methylthio)benzothiazole was alkylated withmethyl p-toluenesulfonate and then condensed with intermediateN-[4-ethylamino-3-(3-furan-2-ylmethyl-4-oxothiazolidin-2-ylideneamino)phenyl]-2-methoxyacetamide.¹H-NMR (CDCl₃): δ 8.09 (1H, s), 7.28-7.38 (3H, m), 7.15 (1H, dd), 6.76(1H, dd), 6.64 (1H, d), 6.44 (1H, d), 6.33 (1H, m), 5.16 (2H, s), 4.14(2H, m), 4.01 (2H, s), 3.77 (2H, m), 3.72 (3H, s), 3.51 (3H, s), 3.44(3H, s), 3.15 (2H, q), 1.23 (3H, t); MS(ESI): 624 (MH⁺).

EXAMPLE 163 Preparation of2-(5-Acetyl-2-ethylaminophenylimino)-3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]thiazolidin-4-one

The title compound was synthesized in a manner similar to that describedin Example 146 by condensing 3′-amino-4′-(ethylamino)acetophenone with3-benzyl-5-[5-(2-methoxyethoxy)-3-methylbenzothiazol-2-ylidene]-2-methylthio-4-oxo-2-thiazoliump-toluenesulfonate. MS(ESI): 546 (MH⁺).

EXAMPLE 164 Preparation ofN-(3-{3-Benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-methoxyacetamide

The title compound was synthesized in a manner similar to that describedin Example 146 by replacing2-dimethylamino-4′-ethylamino-3′-nitroacetanilide with4′-ethylamino-2-methoxy-3′-nitroacetanilide. MS(ESI): 634 (MH⁺).

EXAMPLE 165 A. Preparation ofN-(3-{5-[5-(2-Azidoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-benzyl-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylaminoacetamide

To a 50 mL flask was added the product of Example 145 (225 mg, 345μmol), anhydrous DMF (8 mL), sodium azide (112 mg, 1.73 mmol), andsodium iodide (15 mg, 103 μmol). The reaction slurry was heated at 70°C. for 6 h under N₂. The reaction mixture was diluted with EtOAc (70mL), washed with H₂O (2×30 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure to provide the title compound.MS(ESI): 658 (MH⁺).

B. Preparation ofN-(3-{5-[5-(2-Aminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-benzyl-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylaminoacetamide

To a solution of the aboveN-(3-{5-[5-(2-azidoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-benzyl-4-oxothiazolidin-2-ylideneamino}-4-ethylamino-phenyl)-2-dimethylaminoacetamide(0.34 mmol) in THF (13 mL) was added triphenylphosphine (100 mg, 380mmol) and H₂O (20 mL). The solution was stirred 48 h at roomtemperature. The solvent was removed under reduced pressure, and thecrude material was chromatographed (silica gel, 0-5% MeOH/DCM) to affordthe title compound (157 mg, 72% overall).

¹H-NMR (CDCl₃): δ 8.85 (1H, s), 7.48 (2H, d), 7.27-7.37 (5H, m), 7.13(1H, dd), 6.74 (1H, dd), 6.60 (1H, d), 6.55 (1H, d), 5.17 (2H, s), 4.03(2H, t), 3.73 (3H, s), 3.11 (2H, t), 3.06 (2H, s), 3.00 (2H, q), 2.37(6H, s), 1.39 (2H, t), 1.04 (3H, t); MS(ESI): 631 (MH⁺).

EXAMPLE 166 A. Preparation of 2-Dimethylamino-3′-nitroacetanilide

The title compound was prepared from 3-nitroaniline in a manner similarto that described in Example 139. ¹H-NMR (CDCl₃): δ 9.04 (1H, br s),8.39 (1H, t), 8.06 (1H, dd), 7.96 (1H, dd), 7.50 (1H, t), 3.13 (2H, s),2.41 (6H, s).

B. Preparation of2-Dimethylamino-N-[3-(3-furan-2-ylmethyl-4-oxothiazolidin-2-ylideneamino)phenyl]acetamide

In a manner similar to that described in Example 52, the title compoundwas prepared from 2-furfuryl isothiocyanate and3′-amino-2-(dimethylamino)acetanilide, derived from2-dimethylamino-3′-nitroacetanilide. MS(ESI): 373 (MH⁺).

C. Preparation of2-Dimethylamino-N-{3-[3-furan-2-ylmethyl-5-(5-methoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-phenyl}acetamide

In a manner similar to Example 45, 2-mercapto-5-methoxybenzothiazole wasalkylated with methyl p-toluenesulfonate and then condensed with2-dimethylamino-N-[3-(3-furan-2-ylmethyl-4-oxothiazolidin-2-ylideneamino)-phenyl]acetamide.MS(ESI): 550 (MH⁺).

EXAMPLE 167 Preparation of3-(3′-Benzyl-3,4,5-trimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with 3-chloro-2-butanone.

MS(ESI): 476 (MH⁺).

EXAMPLE 168 Preparation of3-[3-Benzyl-5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with 2-chlorocyclohexanone.MS(ESI): 502 (MH⁺).

EXAMPLE 169 Preparation of3-(3′-Benzyl-4-ethyl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with 1-bromo-2-butanone.

MS(ESI): 476 (MH⁺).

EXAMPLE 170 Preparation of3-[3′-Benzyl-3-methyl-4-(4-nitrophenyl)-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-4′-nitroacetophenone. MS(ESI): 569 (MH⁺).

EXAMPLE 171 Preparation of3-[3′-Benzyl-4-(4-fluorophenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-4′-fluoroacetophenone. MS(ESI): 542 (MH⁺).

EXAMPLE 172 Preparation of3-[3′-Benzyl-4-(4-chloro-phenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-4′-chloroacetophenone. MS(ESI): 558 (MH⁺).

EXAMPLE 173 Preparation of3-(3′-Benzyl-3-methyl-4′-oxo-4-p-tolyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-4′-methylacetophenone. MS(ESI): 538 (MH⁺).

EXAMPLE 174 Preparation of3-[3′-Benzyl-4-(4-methoxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-4′-methoxyacetophenone. MS(ESI): 554 (MH⁺).

EXAMPLE 175 Preparation of3-(5-Acetyl-3′-benzyl-3,4-dimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with3-chloro-2,4-pentanedione. MS(ESI): 504 (MH⁺).

EXAMPLE 176 Preparation of3-[3-Benzyl-5-(3-methyl-3,4,5,6-tetrahydrocyclopentathiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-chlorocyclopentanone. MS(ESI): 488 (MH⁺).

EXAMPLE 177 Preparation of3-(3′-Benzyl-3-methyl-4′-oxo-4,5-diphenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-chloro-2-phenylacetophenone. MS(ESI): 600 (MH⁺).

EXAMPLE 178 Preparation of3-(3′-Benzyl-3,4-dimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with chloroacetone.

MS(ESI): 462 (MH⁺).

EXAMPLE 179 Preparation of4-Ethylamino-3-[5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)-4-oxo-3-pyridin-3-ylmethylthiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to Example 168 bycondensing intermediate3-methyl-2-methylthio-4,5,6,7-tetrahydrobenzothiazol-3-iump-toluenesulfonate with4-ethylamino-3-(4-oxo-3-pyridin-3-ylmethylthiazolidin-2-ylideneamino)benzonitrile.MS(ESI): 503 (MH⁺).

EXAMPLE 180 A. Preparation of Methyl4-[2-(5-Acetyl-2-ethylaminophenylimino)-4-oxothiazolidin-3-ylmethyl]benzoate

In a manner similar to Example 52, the title compound was prepared from3′-amino-4′-ethylaminoacetophenone and methyl4-(isothiocyantomethyl)benzoate—generated from methyl4-(aminomethyl)benzoate hydrochloride and thiophosgene. ¹H-NMR (CDCl₃):δ 8.04 (2H, d), 7.69 (1H, m), 7.58 (1H, s), 7.47 (2H, d), 6.52 (1H, d),5.10 (2H, s), 3.96 (2H, s), 3.92 (3H, s), 3.05 (2H, q), 2.49 (3H, s),1.03 (3H, t).

B. Preparation of Methyl4-[2-(5-Acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoate

The title compound was prepared from intermediate4-[2-(5-acetyl-2-ethylaminophenylimino)-4-oxothiazolidin-3-ylmethyl]benzoicacid methyl ester and 3-methyl-2-(methylthio)benzothiazol-3-iump-toluenesulfonate in a manner similar to Example 45. ¹H-NMR (CDCl₃): δ8.03 (2H, d), 7.64-7.70 (2H, m), 7.49-7.55 (3H, m), 7.36 (1H, m), 7.20(1H, m), 7.08 (1H, d), 6.51 (1H, d), 5.24 (2H, s), 4.15 (1H, br t), 3.91(3H, s), 3.80 (3H, s), 3.04 (2H, m), 2.51 (3H, s), 1.01 (3H, s);MS(ESI): 573 (MH⁺).

EXAMPLE 181 Preparation of Methyl4-[2-(5-Acetyl-2-ethylamino-phenylimino)-5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoate

The title compound was prepared in a manner similar to Example 168 bycondensing intermediate3-methyl-2-methylthio-4,5,6,7-tetrahydrobenzothiazol-3-iump-toluenesulfonate with4-[2-(5-acetyl-2-ethylaminophenylimino)-4-oxothiazolidin-3-ylmethyl]benzoic acid methyl ester.

MS(ESI): 577 (MH⁺).

EXAMPLE 182 Preparation of4-[2-(5-Acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoicAcid

The product of Example 180 was saponified under conditions similar tothat described in Example 29 to afford the title compound. MS(ESI): 559(MH⁺).

EXAMPLE 183 Preparation of3-[3-Benzyl-5-(1-methyl-4,5,6,7-tetrahydro-1H-thiazolo[5,4-c]pyridin-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with3-bromo-4-oxopiperidine-1-carboxylic acid 9H-fluoren-9-ylmethylester—synthesized according to a published procedure [J. Med. Chem.1998, 41, 1409-1416].

¹H-NMR (CDCl₃): δ 7.39-7.43 (2H, m), 7.33 (2H, m), 7.24-7.29 (2H, m),7.20 (1H, d), 6.47 (1H, d), 5.15 (2H, s), 4.28 (1H, br t), 3.81 (2H, brs), 3.63 (3H, s), 3.22 (2H, br s), 2.99 (2H, q), 2.49 (2H, br s), 1.01(3H, t); MS(ESI): 503 (MH⁺).

EXAMPLE 184 Preparation of Methyl3-[2-(5-Acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoate

To a solution of methyl 3-(bromomethyl)benzoate (1.0 g, 4.4 mmol) inanhydrous DMF (10 mL) was added sodium azide (285 mg, 4.4 mmol). Theresulting mixture was heated at 50° C. for 2 h, cooled, diluted withCHCl₃ (100 mL), washed with water (5×50 mL), dried (MgSO₄) andconcentrated under reduced pressure to yield methyl3-(azidomethyl)benzoate (0.84 g, quant.), which was used withoutpurification. ¹H-NMR (CDCl₃): δ 8.01 (2H, m), 7.44-7.54 (2H, m), 4.42(2H, s), 3.94 (3H, s).

Methyl 3-(azidomethyl)benzoate was transformed into its amine(Staudinger conditions) and then converted into its isocyanate in amanner similar to Example 45. The title compound then was prepared in amanner similar to that described in Example 180 by replacing methyl4-(isothiocyantomethyl)benzoate with methyl3-(isothiocyantomethyl)benzoate.

¹H-NMR (CDCl₃): δ 8.13 (1H, br s), 7.98 (1H, d), 7.60-7.70 (3H, m), 7.53(1H, d), 7.43 (1H, m), 7.36 (1H, m), 7.20 (1H, m), 7.07 (1H, d), 6.52(1H, d), 5.24 (2H, s), 4.20 (1H, br t), 3.90 (3H, s), 3.79 (3H, s), 3.05(2H, m), 2.51 (3H, s), 1.01 (3H, t); MS(ESI): 573 (MH⁺).

EXAMPLE 185 Preparation of3-[2-(5-Acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoicAcid

The product of Example 184 was saponified under conditions similar tothat described in Example 29 to afford the title compound. MS(ESI): 559(MH⁺).

EXAMPLE 186 Preparation of2-(5-Acetyl-2-ethylaminophenylimino)-3-benzyl-5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to Example 168 bycondensing intermediate3-methyl-2-methylthio-4,5,6,7-tetrahydrobenzothiazol-3-iump-toluenesulfonate with2-(5-acetyl-2-ethylaminophenylimino)-3-benzylthiazolidin-4-one. MS(ESI):519 (MH⁺).

EXAMPLE 187 Preparation of3-(3′-Benzyl-4-biphenyl-4-yl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-4′-phenylacetophenone. MS(ESI): 600 (MH⁺).

EXAMPLE 188 Preparation of3-(3′-Benzyl-3-methyl-4-naphthalen-2-yl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-2′-acetonaphthone. MS(ESI): 574 (MH⁺).

EXAMPLE 189 Preparation of3-[3′-Benzyl-4-(4-bromophenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2,4′-dibromoacetophenone. MS(ESI): 602 (MH⁺).

EXAMPLE 190 Preparation of3-[3′-Benzyl-3-methyl-4-(2-nitrophenyl)-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-2′-nitroacetophenone. MS(ESI): 569 (MH⁺).

EXAMPLE 191 Preparation of2-(5-Acetyl-2-ethylaminophenylimino)-5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)-3-pyridin-3-ylmethylthiazolidin-4-one

The title compound was prepared in a manner similar to Example 168 bycondensing intermediate3-methyl-2-methylthio-4,5,6,7-tetrahydrobenzothiazol-3-iump-toluenesulfonate with2-(5-acetyl-2-ethylaminophenylimino)-3-pyridin-3-ylmethyl-thiazolidin-4-one.MS(ESI): 520 (MH⁺).

EXAMPLE 192 Preparation of3-[3′-Benzyl-4-(2-methoxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-2′-methoxyacetophenone. MS(ESI): 554 (MH⁺).

EXAMPLE 193 Preparation of3-[3′-Benzyl-4-(3-fluorophenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-3′-fluoroacetophenone. MS(ESI): 542 (MH⁺).

EXAMPLE 194 Preparation of3-[3′-Benzyl-3-methyl-4′-oxo-4-(4-trifluoromethylphenyl)-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-4′-trifluoromethyl-acetophenone. MS(ESI): 592 (MH⁺).

EXAMPLE 195 Preparation of3-[3′-Benzyl-3-methyl-4′-oxo-4-(4-trifluoromethoxyphenyl)-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-4′-(trifluoromethoxy)acetophenone. MS(ESI): 608 (MH⁺).

EXAMPLE 196 Preparation of3-[3′-Benzyl-4-(2,4-dimethoxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-2′,4′-dimethoxyacetophenone. MS(ESI): 584 (MH⁺).

EXAMPLE 197 Preparation of3-(3′-Benzyl-5-ethyl-3-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with 2-bromobutyrophenone.MS(ESI): 552 (MH⁺).

EXAMPLE 198 Preparation of3-[3′-Benzyl-3-methyl-4′-oxo-4-(2-trifluoromethylphenyl)-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-2′-(trifluoromethyl)acetophenone. MS(ESI): 592 (MH⁺).

EXAMPLE 199 Preparation of3-[3′-Benzyl-4-(3-bromophenyl)-3,5-dimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2,3′-dibromopropiophenone. MS(ESI): 617 (MH⁺).

EXAMPLE 200 Preparation of3-[3′-Benzyl-4-(3-methoxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with2-bromo-3′-methoxyacetophenone. MS(ESI): 554 (MH⁺).

EXAMPLE 201 Preparation of3-Benzyl-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxyisopropyl)-phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 52 by replacing aniline with4-(1,1,1,3,3,3-hexafluoro-2-hydroxyisopropyl)aniline. MS(ESI): 596(MH⁺).

EXAMPLE 202 Preparation of3-(3′-Benzyl-4-chloromethyl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with 1,3-dichloroacetone.

MS(ESI): 496 (MH⁺).

EXAMPLE 203 Preparation of3′-Benzyl-2′-(5-cyano-2-ethylaminophenylimino)-3-methyl-4′-oxo-3′,4′-dihydro-3H,2′H-[2,5′]bithiazolylidene-4-carboxylicAcid Ethyl Ester

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with ethyl bromopyruvate.

MS(ESI): 520 (MH⁺).

EXAMPLE 204 Preparation of3-(4,3′-Dibenzyl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with1-chloro-3-phenylpropan-2-one. MS(ESI): 538 (MH⁺).

EXAMPLE 205 Preparation of3′-Benzyl-2′-(5-cyano-2-ethylaminophenylimino)-3-methyl-4′-oxo-3′,4′-dihydro-3H,2′H-[2,5′]bithiazolylidene-4-carboxylicAcid

The product of Example 203 was saponified under conditions similar tothat described in Example 29 to afford the title compound. MS(ESI): 492(MH⁺).

EXAMPLE 206 Preparation of3-Benzyl-2-[2-ethylamino-5-(1-hydroxyethyl)phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The product of Example 38 was reduced with sodium borohydride in 1:1MeOH/THF and chromatographed (TEA-washed silica gel, 0-10% MeOH/DCM) toafford the title compound. ¹H-NMR (CDCl₃): δ 7.47-7.54 (3H, m),7.28-7.37 (4H, m), 7.17 (1H, m), 6.99-7.06 (3H, m), 6.57 (1H, d), 5.19(2H, s), 4.80 (1H, q), 3.76 (3H, s), 3.01 (2H, q), 1.48 (3H, d), 1.04(3H, s); MS(ESI): 517 (MH⁺).

EXAMPLE 207 Preparation of3-[3′-Benzyl-4-(2-hydroxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The product of Example 192 was treated with boron tribromide in DCM at25° C. After 15 min the product mixture was quenched with brine,concentrated and chromatographed (silica gel, 0-10% MeOH/DCM) to yieldthe title compound. MS(ESI): 540 (MH⁺).

EXAMPLE 208 Preparation of3-Benzyl-2-[2-ethylamino-5-(1-hydroxyiminoethyl)phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

To the product of Example 38 was added hydroxylamine hydrochloride (2equiv) and pyridine. The resulting mixture was heated at 80° C. for 24h, cooled, concentrated and chromatographed (TEA-washed silica gel,0-50% EtOAc/Hex) to give the title compound. ¹H-NMR (DMSO-d₆): δ 11.07(1H, s), 7.88 (1H, s), 7.67 (2H, m), 7.53 (1H, d), 7.39 (2H, m),7.21-7.33 (5H, m), 7.09-7.14 (1H, m), 5.05 (2H, s), 3.92 (2H, q), 3.27(3H, s), 2.23 (3H, s), 1.03 (3H, t); MS(ESI): 530 (MH⁺).

EXAMPLE 209 Preparation of3-Benzyl-2-[2-ethylamino-5-(1-methoxyiminoethyl)phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 208 by replacing hydroxylamine hydrochloride withO-methylhydroxylamine hydrochloride. MS(ESI): 544 (MH⁺).

EXAMPLE 210 Preparation of3-Benzyl-2-[5-(1-benzyloxyiminoethyl)-2-ethylaminophenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample-208 by replacing hydroxylamine hydrochloride withO-benzylhydroxylamine hydrochloride. MS(ESI): 620 (MH⁺).

EXAMPLE 211 Preparation of3-Benzyl-2-{2-ethylamino-5-[1-(phenylhydrazono)ethyl]-phenylimino}-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 208 by replacing hydroxylamine hydrochloride withphenylhydrazine. MS(ESI): 605 (MH⁺).

EXAMPLE 212 Preparation of3-(4,3′-Dibenzyl-3,5-dimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with3-chloro-1-phenylbutan-2-one. MS(ESI): 552 (MH⁺).

EXAMPLE 213 Preparation of3-[3-Cyclohexylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 83 by replacing 3-picolyl isothiocyanate hydrobromide withcyclohexylmethyl isothiocyanate. MS(ESI): 504 (MH⁺).

EXAMPLE 214 Preparation of3-[3′-Benzyl-4-(3-hydroxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared from the product of Example 200 in amanner similar to that described in Example 207. MS(ESI): 540 (MH⁺).

EXAMPLE 215 Preparation of3-[3′-Benzyl-4-(4-hydroxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared from the product of Example 174 in amanner similar to that described in Example 207. MS(ESI): 540 (MH⁺).

EXAMPLE 216 Preparation of3-(3′-Benzyl-3,4-dimethyl-4′-oxo-5-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 52 by replacing 2-bromopropiophenone with1-chloro-1-phenylpropan-2-one—generated in situ by addition ofmethylmagnesium chloride to chlorophenylacetyl chloride (−78 to 25° C.).MS(ESI): 538 (MH⁺).

EXAMPLE 217 Preparation of2′-(5-Acetyl-2-ethylaminophenylimino)-3′-benzyl-3,5-dimethyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 52 by replacing 3-amino-4-ethylaminobenzonitrile with3′-amino-4′-ethylaminoacetophenone. MS(ESI): 555 (MH⁺).

EXAMPLE 218 Preparation of2′-(5-Acetyl-2-ethylaminophenylimino)-3′-benzyl-3,4-dimethyl-5-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 217 by replacing 2-bromopropiophenone with1-chloro-1-phenylpropan-2-one. MS(ESI): 555 (MH⁺).

EXAMPLE 219 Preparation of2′-(5-Acetyl-2-ethylaminophenylimino)-3′-benzyl-4-(4-methoxyphenyl)-3,5-dimethyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 217 by replacing 2-bromopropiophenone with2-bromo-4′-methoxypropiophenone. MS(ESI): 585 (MH⁺).

EXAMPLE 220 Preparation of2′-(5-Acetyl-2-ethylaminophenylimino)-4,3′-dibenzyl-3-methyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 217 by replacing 2-bromopropiophenone with1-chloro-3-phenylpropan-2-one. MS(ESI): 555 (MH⁺).

EXAMPLE 221 Preparation of2′-(5-Acetyl-2-ethylaminophenylimino)-3′-benzyl-4-(2-methoxyphenyl)-3,5-dimethyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 217 by replacing 2-bromopropiophenone with2-bromo-2′-methoxypropiophenone. MS(ESI): 585 (MH⁺).

EXAMPLE 222 Preparation of3-{3-Benzyl-5-[5-(2-dimethylaminoacetyl)-1-methyl-4,5,6,7-tetrahydro-1H-thiazolo[5,4-c]pyridin-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

To the product of Example 183 in CHCl₃ was added N,N-dimethylaminoacetylchloride and TEA. After 4 h the product mixture was concentrated andchromatographed (silica gel, 0-40% EtOAc/Hex) to yield the titlecompound. ¹H-NMR (CDCl₃): δ 7.39-7.44 (2H, m), 7.33 (2H, m), 7.23-7.30(2H m), 7.19 (1H, br s), 6.47 (1H, d), 5.15 (2H, s), 4.61 (1H, br s),4.51 (1H, br s), 4.27 (1H, m), 3.92 (2H, m), 3.64 (3H, br s), 3.22 (1H,br s), 3.16 (1H, br s), 2.99 (2H, m), 2.63 (1H, br s), 2.56 (1H, br s),2.31 (3H, s), 2.28 (3H, s), 1.01 (3H, t); MS(ESI): 588 (MH⁺).

EXAMPLE 223 Preparation of2′-5-Acetyl-2-ethylaminophenylimino)-3′-benzyl-4-(3-methoxyphenyl)-3,5-dimethyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 217 by replacing 2-bromopropiophenone with2-bromo-3′-methoxypropiophenone. MS(ESI): 585 (MH⁺).

EXAMPLE 224 Preparation of2′-(5-Acetyl-2-ethylaminophenylimino)-3′-benzyl-4-(3-hydroxyphenyl)-3,5-dimethyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared from the product of Example 223 in amanner similar to that described in Example 207. MS(ESI): 571 (MH⁺).

EXAMPLE 225 Preparation of2′-(5-Acetyl-2-ethylaminophenylimino)-3,3′-dibenzyl-5-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 52 by replacing triethylammonium methyldithiocarbamate withtriethylammonium benzyldithiocarbamate—generated from benzylamine,carbon disulfide and TEA. MS(ESI): 631 (MH⁺).

EXAMPLE 226 Preparation ofN-(3-{3-Benzyl-5-[5-(2-acetoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylamino-acetamide

To the product of Example 145 (21 mg, 32 μmol) in acetone (2 mL) wasadded tetra-n-butylammonium iodide (24 mg, 65 μmol). The solution wasstirred at 40° C. for 17 h prior to the addition of sodium acetate (50mg, 0.64 mmol). The reaction solution was heated at 75° C. for 48 h.After cooling the solution was diluted with EtOAc (25 mL), washed withsatd NaHCO₃ (20 mL) and water (2×20 mL), dried over Na₂SO₄, andconcentrated under reduced pressure. The crude sample waschromatographed (silica gel, DCM) to provide the title compound (7 mg,33%). ¹H-NMR (CDCl₃) δ 7.87 (1H, s), 7.60 (1H, dd), 7.30-7.35 (3H, m),7.17-7.22 (3H, m), 6.60 (1H, dd), 6.48 (1H, d), 5.27 (2H, s), 4.72 (1H,s), 4.39 (2H, t), 4.16 (2H, t), 3.69 (2H, q), 3.16 (2H, s), 3.08 (3H,s), 2.43 (6H, s), 2.06 (3H, s), 0.91 (3H, t); MS(ESI): 675 (MH⁺).

EXAMPLE 227 Preparation of2′-(5-Acetyl-2-ethylaminophenylimino)-3′-benzyl-3-(2-methoxyethyl)-5-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 52 by replacing triethylammonium methyldithiocarbamate withtriethylammonium 2-methoxyethyldithiocarbamate—generated from2-methoxy-ethylamine, carbon disulfide and TEA. MS(ESI): 599 (MH⁺).

EXAMPLE 228 Preparation of2′-(5-Acetyl-2-ethylaminophenylimino)-3′-benzyl-3-(3-methoxypropyl)-5-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 52 by replacing triethylammonium methyldithiocarbamate withtriethylammonium 3-methoxypropyldithiocarbamate—generated from2-methoxy-propylamine, carbon disulfide and TEA. MS(ESI): 613 (MH⁺).

EXAMPLE 229 Preparation of[2′-(5-Acetyl-2-ethylaminophenylimino)-3′-benzyl-5-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-2′H-[2,5′]bithiazolyliden-3-yl]aceticAcid Methyl Ester

The title compound was prepared in a manner similar to that described inExample 52 by replacing triethylammonium methyldithiocarbamate withtriethylammonium methoxycarbonylmethyldithiocarbamate—generated fromglycine methyl ester, carbon disulfide and TEA. MS(ESI): 613 (MH⁺).

EXAMPLE 230 Preparation of[2′-(5-Acetyl-2-ethylaminophenylimino)-3′-benzyl-5-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-2′H-[2,5′]bithiazolyliden-3-yl]aceticAcid

The product of Example 229 was saponified under conditions similar tothat described in Example 29 to afford the title compound. MS(ESI): 599(MH⁺).

EXAMPLE 231 A. Preparation of2-(5-Methyl-4-phenyl-2-thioxothiazol-3-yl)ethyl Acetate

3-(2-Hydroxyethyl)-5-methyl-4-phenyl-3H-thiazole-2-thione was preparedin a manner similar to that described in Example 52 by replacingtriethylammonium methyldithiocarbamate with triethylammonium2-hydroxyethyldithiocarbamate—generated from ethanolamine, carbondisulfide and TEA.

Intermediate 3-(2-hydroxyethyl)-5-methyl-4-phenyl-3H-thiazole-2-thionewas treated with acetic anhydride (1 equiv) and TEA (2 equiv) in CHCl₃.After 12 h the product mixture was concentrated and chromatographed(silica gel, 0-40% EtOAc/Hex) to afford the title compound. ¹H-NMR(CDCl₃): δ 7.50-7.55 (3H, m), 7.28-7.32 (2H, m), 4.32 (2H, t), 4.26 (2H,t), 2.03 (3H, s), 1.93 (3H, s).

B. Preparation of2-[2′-(5-Acetyl-2-ethylaminophenylimino)-3′-benzyl-5-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-2′H-[2,5′]bithiazolyliden-3-yl]ethylAcetate

In a manner similar to that described in Example 52, intermediate2-(5-methyl-4-phenyl-2-thioxothiazol-3-yl)ethyl acetate was alkylatedwith methyl p-toluenesulfonate and condensed with2-(5-acetyl-2-ethylaminophenylimino)-3-benzylthiazolidin-4-one to yieldthe title compound. ¹H-NMR (CDCl₃): δ 7.63-7.67 (2H, m), 7.44-7.51 (5H,m), 7.28-7.37 (5H, m), 6.50 (1H, d), 5.19 (2H, s), 4.30 (1H, br t), 4.03(4H, m), 3.06 (2H, m), 2.48 (3H, s), 2.05 (3H, s), 1.89 (3H, s), 1.05(3H, t); MS(ESI): 627 (MH⁺).

EXAMPLE 232 Preparation of2′-(5-Acetyl-2-ethylaminophenylimino)-3′-benzyl-3-(2-hydroxyethyl)-5-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The product of Example 231 was saponified under conditions similar tothat described in Example 29 to afford the title compound. MS(ESI): 585(MH⁺).

EXAMPLE 233 A. Preparation of3′-Benzyl-3,5-dimethyl-4-phenyl-2′-thioxo-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one

The title compound was prepared in a manner similar to that described inExample 1 by replacing 2-methylthiobenzothiazole with3,5-dimethyl-4-phenyl-3H-thiazole-2-thione. ¹H-NMR (CDCl₃): δ 7.50-7.58(5H, m), 7.23-7.32 (5H, m), 5.39 (2H, s), 3.54 (3H, s), 2.11 (3H, s).

B. Preparation ofN-[3-(3′-Benzyl-3,5-dimethyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminophenyl]-2-methoxyacetamide

Likewise as described in Example 1, intermediate3′-benzyl-3,5-dimethyl-4-phenyl-2′-thioxo-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-onewas alkylated with methyl p-toluenesulfonate and condensed withN-(3-amino-4-ethylaminophenyl)-2-methoxyacetamide to afford the titlecompound. ¹H-NMR (CDCl₃): δ 8.00 (1H, br s), 7.42-7.51 (5H, m),7.30-7.37 (3H, m), 7.19-7.26 (3H, m), 7.11 (1H, d), 6.53 (1H, br s),5.18 (2H, s), 3.97 (2H, s), 3.47 (3H, s), 3.42 (3H, s), 2.98 (2H, m),2.06 (3H, s), 1.02 (3H, br t); MS(ESI): 600 (MH⁺).

EXAMPLE 234 Preparation ofN-[3-(3′-Benzyl-3,5-dimethyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminophenyl]-2-dimethylaminoacetamide

The title compound was prepared in a manner similar to that described inExample 233 by replacingN-(3-amino-4-ethylaminophenyl)-2-methoxyacetamide withN-(3-amino-4-ethylaminophenyl)-2-dimethylaminoacetamide. MS(ESI): 613(MH⁺).

EXAMPLE 235 Preparation of3-[3-Cyclohexyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

To a biphasic mixture of cyclohexylamine (2.3 mL, 20 mmol) in CHCl₃ (60mL) and satd aqueous NaHCO₃ (40 mL) was added a solution of CSCl₂ (1.57mL, 20 mmol) in CHCl₃ (5 mL) dropwise at 5° C. The mixture was stirred 1h at 5° C. Methyl thioglycolate (1.9 mL, 20 mmol) was added, and themixture was stirred overnight at 20° C. The organic layer was separated,and the aqueous layer was extracted with CHCl₃. The combined organiclayers were washed with water, 1N HCl, water, satd aqueous NaHCO₃ andthen dried over MgSO₄. Evaporation of solvent under reduced pressuregave a crude material, which was used in the next step withoutpurification.

To a solution of the above product in toluene (80 mL) was added TsOH(100 mg), and the mixture was heated at reflux for 8 h with a droppingfunnel containing 4 Å molecular sieves attached to the flask. Aftercooling, solid was removed by filtration. Evaporation of the filtrategave a crude, which was purified by column chromatography on silica gel,eluting with EtOAc-Hex (0:100 to 3:7) to afford 3-cyclohexylrhodanine(1.24 g). ¹H-NMR (CDCl₃): δ 4.86 (1H, m), 3.82 (2H, s), 2.30 (2H, q),1.86 (2H, m), 1.58-1.72 (3H, m), 1.16-1.42 (3H, m).

The title compound was prepared in a manner similar to that described inExample 32 by replacing 3-benzylrhodanine with 3-cyclohexylrhodanine.

MS(ESI): 490 (MH⁺).

EXAMPLE 236 Preparation of3-[3-Allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 235 by replacing cyclohexylamine with allylamine. MS(ESI): 448(MH⁺).

EXAMPLE 237 Preparation of3-Allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-5-ylimino)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 236 by replacing 3-amino-4-ethylaminobenzonitrile with5-aminoquinoline. MS(ESI): 431 (MH⁺).

EXAMPLE 238 Preparation of3-Allyl-2-(4-hydroxy-5-isopropyl-2-methylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 236 by replacing 3-amino-4-ethylaminobenzonitrile with4-aminothymol hydrochloride. MS(ESI): 452 (MH⁺).

EXAMPLE 239 Preparation of4-Ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-phenylthiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 235 by replacing cyclohexylamine with aniline. MS(ESI): 484(MH⁺).

EXAMPLE 240 Preparation of3-Cyclohexyl-2-(2-hydroxynaphthalen-1-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 235 by replacing 3-amino-4-ethylaminobenzonitrile with1-amino-2-naphthol hydrochloride. MS(ESI): 488 (MH⁺).

EXAMPLE 241 Preparation of3-Allyl-2-(2-hydroxynaphthalen-1-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 236 by replacing 3-amino-4-ethylaminobenzonitrile with1-amino-2-naphthol hydrochloride. MS(ESI): 446 (MH⁺).

EXAMPLE 242 Preparation of2-(4-Cyclohexylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-3-phenylthiazolidin-4-one

The title compound was prepared in a manner similar to that described inExample 239 by replacing 3-amino-4-ethylaminobenzonitrile with4-cyclohexylaniline. MS(ESI): 498 (MH⁺).

EXAMPLE 243 Preparation of3-[3-Benzyl-5-(6-fluoro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 55 by replacing 2-mercapto-5-trifluoromethylbenzothiazole with6-fluoro-2-mercaptobenzothiazole. MS(ESI): 516 (MH⁺).

EXAMPLE 244 Preparation of3-[3-Benzyl-5-(5-chloro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 55 by replacing 2-mercapto-5-trifluoromethylbenzothiazole with5-chloro-2-mercaptobenzothiazole. MS(ESI): 532 (MH⁺).

EXAMPLE 245 Preparation of3-[3-Benzyl-5-(6-ethoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 55 by replacing 2-mercapto-5-trifluoromethylbenzothiazole with6-ethoxy-2-mercaptobenzothiazole. MS(ESI): 542 (MH⁺).

EXAMPLE 246 Preparation of4-Ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-propylthiazolidin-2-ylideneamino]benzonitrile

The title compound was prepared in a manner similar to that described inExample 235 by replacing cyclohexylamine with propylamine. MS(ESI): 450(MH⁺).

EXAMPLE 247 Preparation of3-[3-Benzyl-5-(3-methyl-6-nitro-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 55 by replacing 2-mercapto-5-trifluoromethylbenzothiazole with2-mercapto-6-nitrobenzothiazole. MS(ESI): 543 (MH⁺).

EXAMPLE 248 Preparation ofN-{2-[3-Benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}acetamide

The title compound was prepared in a manner similar to that described inExample 55 by replacing 2-mercapto-5-trifluoromethylbenzothiazole with2-mercapto-6-acetamidobenzothiazole. MS(ESI): 555 (MH⁺).

EXAMPLE 249 Preparation of3-[3-Benzyl-5-(6-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared from the product of Example 245 in amanner similar to that described in Example 57. MS(ESI): 514 (MH⁺).

EXAMPLE 250 Preparation of Ethylcarbamic Acid2-[3-Benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-ylEster

The title compound was prepared in a manner similar to that described inExample 58 by replacing dimethylcarbamoyl chloride with ethylisocyanate.

MS(ESI): 585 (MH⁺).

EXAMPLE 251 Preparation of{2-[3-Benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yloxy}aceticAcid Methyl Ester

To a suspension of K₂CO₃ (41 mg, 5 equiv) in 2-butanone (2 mL) wereadded the product of Example 57 (31 mg, 0.06 mmol) and methyl2-bromoacetate (7 μL, 1.2 equiv). The resulting suspension was heated at75° C. overnight. After cooling, the reaction mixture was filtered, andthe filtrate was evaporated to give a crude material, which was purifiedby chromatography on silica gel, eluting with MeOH-DCM (0:100 to 3:97)to give the title compound (5 mg). ¹H-NMR (CDCl₃): δ 7.63 (1H, d),7.28-7.39 (6H, m), 7.13 (1H, d), 7.08 (1H, d), 6.84 (1H, dd), 6.62 (1H,d), 5.13 (2H, s), 4.98 (1H, t), 4.88 (2H, s), 3.79 (3H, s), 3.68 (3H,s), 3.05 (2H, m), 0.99 (3H, t); MS(ESI): 586 (MH⁺).

EXAMPLE 252 Preparation of2-{2-[3-Benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yloxy}acetamide

The title compound was prepared in a manner similar to that described inExample 251 by replacing methyl 2-bromoacetate with 2-bromoacetamide.

MS(ESI): 571 (MH⁺).

EXAMPLE 253 Preparation of (2-Chloroethyl)carbamic Acid2-[3-Benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-ylEster

The title compound was prepared in a manner similar to that described inExample 250 by replacing ethyl isocyanate with 2-chloroethylisocyanate.

MS(ESI): 619 (MH⁺).

EXAMPLE 254 Preparation of3-{3-Benzyl-5-[3-methyl-5-(2-methylaminoethoxy)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

To the product of Example 57 (62 mg, 0.12 mmol) in anhydrous DMF (2 mL)were added 1,2-dibromoethane (100 mL, 10 equiv) and anhydrous K₂CO₃ (166mg, 10 equiv). The suspension was shaken overnight at 60° C. in a sealedtube. After cooling, the reaction mixture was concentrated under reducedpressure, diluted with DCM and acetone, and filtered. The filtrate wasconcentrated to give a residue, which was purified by chromatography onsilica gel, eluting with MeOH-DCM (1:19) to give a yellow solid, whichwas used in the next step without further purification.

The above material was dissolved in 2M solution of methylamine in THF (3mL) and the solution was heated in a sealed tube for 40 h at 60° C.After cooling, the product mixture was concentrated to give a residue,which was purified by chromatography on silica gel, eluting withMeOH-DCM (1:19 to 1:9) to give the title compound (10 mg). ¹H-NMR(CDCl₃): δ 7.63 (1H, d), 7.28-7.39 (6H, m), 7.13 (1H, d), 7.03 (1H, d),6.85 (1H, dd), 6.62 (1H, d), 5.13 (2H, s), 4.98 (1H, t), 4.12 (2H, t),3.79 (3H, s), 3.05 (3H, m), 2.93 (2H, t), 2.3 (3H, s), 0.99 (3H, t);MS(ESI): 571 (MH⁺).

EXAMPLE 255 Preparation of3-{3-Benzyl-5-[5-(3-hydroxypropoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 59 by replacing 2-bromoethanol with 3-bromopropanol. MS(ESI):572 (MH⁺).

EXAMPLE 256 Preparation of (3-Chloropropyl)carbamic Acid2-[3-Benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-ylEster

The title compound was prepared in a manner similar to that described inExample 250 by replacing ethyl isocyanate with 3-chloropropylisocyanate.

MS(ESI): 633 (MH⁺).

EXAMPLE 257 Preparation of3-(3-Benzyl-5-{3-methyl-5-[2-(4-methylpiperazin-1-yl)-ethoxy]-3H-benzothiazol-2-ylidene}-4-oxothiazolidin-2-ylideneamino)-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 60 by replacing morpholine with 1-methylpiperizine. MS(ESI): 640(MH⁺).

EXAMPLE 258 Preparation of3-{3-Benzyl-5-[3-methyl-5-(2-piperidin-4-ylethoxy)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 60 by replacing morpholine with piperidine. MS(ESI): 625 (MH⁺).

EXAMPLE 259 Preparation of3-{3-Benzyl-5-[5-(2-dimethylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 60 by replacing morpholine with dimethylamine. ¹H-NMR (CDCl₃): δ7.43 (2H, m), 7.33 (1H, d), 7.29 (2H, m), 7.25-7.27 (5H, m), 7.20 (1H,d), 6.80 (1H, dd), 6.70 (1H, d), 6.49 (1H, d), 5.18 (2H, s), 4.22 (1H,t), 4.11 (2H, t), 3.77 (3H, s), 3.00 (2H, m), 2.75 (2H, t), 2.35 (6H,s), 1.02 (3H, t), MS(ESI): 585 (MH⁺).

EXAMPLE 260 Preparation of{2-[3-Benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yloxy}aceticAcid

To the product of Example 57 (158 mg, 0.31 mmol) in anhydrous DMF (5 mL)were added tert-butyl bromoacetate (460 μL, 10 equiv) and anhydrousK₂CO₃ (425 mg, 10 equiv). The suspension was heated at 80° C. undernitrogen for 16 h. After cooling, resulting solids were removed byfiltration. The filtrate was concentrated to give a residue, which waspurified by chromatography on silica gel, eluting with MeOH-DCM (5:95)to give the product, which was used in the next step without furtherpurification.

The above product was dissolved in a 1:1 mixture of TFA/DCM (2 mL) andthe solution was stirred for 1 h at 20° C. Evaporation of solvent gave aresidue, which was purified by chromatography on silica gel, elutingwith MeOH-DCM (5:95) to give the title compound (35 mg, 75%). ¹H-NMR(CDCl₃): δ 7.61 (1H, m), 7.28-7.39 (6H, m), 7.13 (1H, d), 7.05 (1H, d),6.82 (1H, dd), 6.62 (1H, d), 5.14 (2H, s), 4.95 (1H, t), 4.76 (2H, t),3.79 (3H, s), 3.05 (2H, m), 0.99 (3H, t), MS(ESI): 572 (MH⁺).

EXAMPLE 261 Preparation of3-{3-Benzyl-5-[6-(2-hydroxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 59 by replacing the product of Example 57 with the product ofExample 249. MS(ESI): 558 (MH⁺).

EXAMPLE 262 Preparation of3-{3-Benzyl-5-[6-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in the same manner as described inExample 261 in the presence of excess methyl p-toluenesulfonate.MS(ESI): 572 (MH⁺).

EXAMPLE 263 Preparation of3-{3-Benzyl-5-[3-methyl-6-(2-morpholin-4-ylethoxy)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 60 by replacing the product of Example 60 with the product ofExample 261. MS(ESI): 627 (MH⁺).

EXAMPLE 264 Preparation of3-{3-Benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in the same manner as described inExample 59 in the presence of excess methyl p-toluenesulfonate. MS(ESI):572 (MH⁺).

EXAMPLE 265 A. Preparation of 4-Methoxy-2-methylthiobenzothiazole

2-Amino-4-methoxybenzothiazole (3.6 g, 20 mmol) was dissolved in warmH₃PO₄ (120 mL). The resulting homogeneous solution was cooled to −8° C.,and a solution of NaNO₂ (8.28 g, 120 mmol) in H₂O (50 mL) was addeddropwise with stirring such that the temperature was not allowed to riseabove −4° C. The resulting dark-red syrup was added slowly to H₃PO₂ (50%in H₂O, 60 mL) at 0° C. with stirring. After the addition was complete,the mixture was allowed to warm to ambient temperature until gasevolution had ceased. The solution was diluted with ice-water,cautiously neutralized with solid Na₂CO₃, and extracted with CHCl₃(3×200 mL). The combined extracts were washed with water (2×200 mL),dried over Na₂SO₄, and concentrated under reduced pressure to give a redsolid (2.87 g), which was purified by chromatography on silica gel,eluting with EtOAc-Hex (0:100 to 30:70) to yield 4-methoxybenzothiazole(2.14 g, 65%) as a yellow solid. ¹H-NMR (CDCl₃): δ 8.90 (1H, s), 7.52(1H, d), 7.38 (1H, t), 6.93 (1H, d), 4.06 (3H, s).

To a solution of 4-methoxybenzothiazole (495 mg, 3.0 mmol) in anhydrousTHF (12 mL) at −78° C. was added BuLi (2.5 mL, 1.6M in hexanes, 4.0mmol) dropwise. The resulting red solution was stirred at −78° C. for 2h under N₂. Methyl disulfide (0.55 mL, 6.0 mmol) was added dropwise at−78° C. and the mixture was allowed to warm to ambient temperatureovernight. The reaction mixture was combined with water and thenextracted with EtOAc. The combined extracts were washed with brine,dried over Na₂SO₄, and concentrated under reduced pressure to afford thetitle compound as a yellow oil (632 mg, 100%), which solidified uponstanding and was used without purification. ¹H-NMR (CDCl₃): δ 7.35 (1H,d), 7.24 (1H, q), 6.86 (1H, d), 4.06 (3H, s), 2.79 (3H, s).

B. Preparation of3-{3-Benzyl-5-[3-methyl-4-methoxy-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}4-ethylaminobenzonitrile

To a suspension of the 4-methoxy2-methylthiobenzothiazole (0.60 g, 2.8mmol) in anhydrous anisole (8 mL) was added methyl p-toluenesulfonate(1.4 mL, 9.0 mmol) and the suspension was heated at 130° C. for 3.5 h.After cooling to 20° C., MeCN (5 mL),3-(3-benzyl-4-oxothiazolidin-2-ylideneamino)-4-ethylaminobenzonitrile(119 mg, 0.34 mmol) and TEA (2.0 mL, 14 mmol) were added. The suspensionwas stirred for 5 h at 80° C. After cooling to ambient temperature,yellow solids were collected by filtration, washed with MeCN and driedunder high vacuum to afford the title compound (123 mg, 69%). ¹H-NMR(CDCl₃): δ 7.45-7.11 (9H, m), 6.88-6.85 (1H, m), 6.48 (1H, d), 5.17 (2H,s), 4.08 (3H, s), 3.92 (3H, s), 3.02-2.97 (2H, m), 1.02 (3H, t);MS(ESI): 528 (MH⁺).

EXAMPLE 266 Preparation of3-{3-Benzyl-5-[3-methyl-4-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 265 by starting from 2-amino-4-methylbenzothiazole. ¹H-NMR(CDCl₃): δ 7.46-7.06 (10H, m), 6.49 (1H, d), 5.17 (2H, s), 3.88 (3H, s),3.04-2.97 (2H, m), 2.62 (3H, s), 1.03 (3H, t); MS(ESI): 512 (MH⁺).

EXAMPLE 267 Preparation of3-{3-Benzyl-5-[3-methyl-4-chloro-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 265 by starting from 2-amino-4-chlorobenzothiazole. ¹H-NMR(CDCl₃): δ 7.45-7.08 (10H, m), 6.50 (1H, d), 5.17 (2H, s), 4.01 (3H, s),3.04-2.98 (2H, m), 1.03 (3H, t); MS(ESI): 532 (MH⁺).

EXAMPLE 268 Preparation of3-{3-Benzyl-5-[3-methyl-6-trifluoromethoxy-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 265 by starting from 2-amino-6-(trifluoromethoxy)benzothiazole.

¹H-NMR (CDCl₃): δ 7.44-7.18 (9H, m), 7.06 (1H, d), 6.49 (1H, d), 5.17(2H, s), 3.81 (3H, s), 3.04-2.97 (2H, m), 1.03 (3H, t); MS(ESI): 582(MH⁺).

EXAMPLE 269 Preparation of3-[3-Benzyl-5-(3,5,6-trimethyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExample 265 by starting from 2-amino-5,6-dimethylbenzothiazole. ¹H-NMR(CDCl₃): δ 7.44-7.20 (8H, m), 6.90 (1H, s), 6.48 (1H, d), 5.17 (2H, s),3.80 (3H, s), 3.03-2.97 (2H, m), 2.35 (3H, s), 2.31 (3H, s), 1.02 (3H,t); MS(ESI): 526 (MH⁺).

EXAMPLE 270 A. Preparation of 5-Acetamidobenzothiazole

To a stirred solution of 4-chloro-3-nitroaniline (17.3 g, 100 mmol) inDCM (150 mL) was added dropwise acetic anhydride (14 mL, 150 mmol) atambient temperature. The mixture was stirred at ambient temperature for2.5 h. The solvent was removed in vacuo, and Et₂O was added to theresidue. The precipitate was collected by filtration, washed with Et₂O,and dried in vacuo to give N-(4-chloro-3-nitrophenyl)acetamide (20.7 g,96%), which was used without further purification.

A suspension of the above compound (13.8 g, 64.3 mmol) and Na₂S.9H₂O(18.6 g, 77.2 mmol) in DMF (100 mL) was stirred at ambient temperatureunder N₂ overnight. The reaction mixture was filtered, and the filtratewas diluted with water (400 mL) and then acidified with conc HCl to pH3. The resulting yellow solids were collected by filtration, washed withwater and dried under high vacuum to afford4′-mercapto-3′-nitroacetanilide (12.0 g, 88%).

A suspension of 4′-mercapto-3′-nitroacetanilide (3.0 g, 14 mmol) and 10%Pd/C (0.6 g) in MeOH (200 mL) was hydrogenated at 60 psi overnight. Thecatalyst was removed by filtration, and the filtrate was concentrated togive 3′-amino-4′-mercaptoacetanilide (2.5 g, 13 mmol), which was used inthe next reaction immediately.

To a solution of intermediate 3′-amino-4′-mercaptoacetanilide in HOAc(50 mL) was added ethoxymethylene malononitrile (1.95 g, 16 mmol) andthe resulting mixture was refluxed at 125° C. for 5 h. After cooling,the product mixture was concentrated under reduced pressure, and theresidue was partitioned between satd aqueous NaHCO₃ and EtOAc. Theaqueous phase was extracted with EtOAc, and the combined extracts werewashed with brine, dried over Na₂SO₄ and concentrated. The residue waspurified by chromatography on silica gel, eluting with EtOAc-Hex (0:100to 50:50) to give the title compound (508 mg, 17%) as a yellow solid.¹H-NMR (DMSO-d₆): δ 9.35 (1H, s), 8.53(1H, s), 8.10 (1H, d), 7.63 (1H,d), 2.15 (3H, s).

B. Preparation of3-[3-Benzyl-5-(3-methyl-5-acetamido-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared using the above 5-acetamidobenzothiazoleas the starting material in a manner similar to that described inExample 265. ¹H-NMR (CDCl₃): δ 7.45-7.21 (8H, m), 6.62 (1H, dd), 6.48(1H, d), 6.34 (1H, d), 5.17 (2H, s), 3.79 (3H, s), 3.02 (3H,s), 3.00(2H, m), 1.02 (3H, t); MS(ESI): 555 (MH⁺).

EXAMPLE 271 A. Preparation of2-Methylthio-6-(trifluoroacetoamido)benzothiazole

To a suspension of 6-amino-2-mercaptobenzothiazole (550 mg, 3.0 mmol) inanhydrous MeCN (15 mL) was added TEA (0.9 mL) and methylp-toluenesulfonate (0.45 mL, 3.0 mmol) at ambient temperature. Themixture turned to a clear solution after a few minutes and was stirredat ambient temperature for 3 h. To the above solution was added dropwiseTFAA (0.65 mL, 4.6 mmol). After 12 h the solution was concentrated underreduced pressure, diluted with EtOAc, washed with water and brine, driedover Na₂SO₄ and concentrated. The resulting residue was purified bychromatography on silica gel, eluting with EtOAc-Hex (0:100 to 10:90) togive the title compound (575 mg, 66%) as a white solid. ¹H-NMR (CDCl₃):δ 8.31 (1H, d), 7.99 (1H, br s), 7.84 (1H, d), 7.35 (1H, dd), 2.80 (3H,s).

B. Preparation ofN-{2-[3-Benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-4-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yl}-2,2,2-trifluoroacetamide

The title compound was prepared in a manner similar to that described inExample 265 by starting with2-methylthio-6-(trifluoroacetamido)benzothiazole. ¹H-NMR (DMSO-d₆): δ7.82 (1H, d), 7.40-7.06 (8H, m), 6.90 (1H, d), 6.48 (1H, d), 6.40 (1H,d), 4.89 (2H, s), 3.57 (3H, s), 2.83 (2H, m), 0.77 (3H, t); MS(ESI): 609(MH⁺).

EXAMPLE 272 Preparation of3-[5-(6-Amino-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

To the product of Example 271 (400 mg, 0.66 mmol) in a mixture ofMeOH/H₂O (12 mL, 5:1 v/v) was added potassium carbonate (553 mg, 4.0mmol). The reaction mixture was stirred at 60° C. for 16 h, and thenconcentrated under reduced pressure. The resulting residue waspartitioned between CHCl₃ and water. The aqueous phase was extractedwith CHCl₃, and the combined extracts were washed with brine, dried overNa₂SO₄, and concentrated to give the title compound (326 mg, 97%) as ayellow solid. ¹H-NMR (DMSO-d₆): δ 7.40-7.28 (6H, m), 7.15-7.13 (2H, m),6.88 (1H, d), 6.66-6.61 (2H, m), 5.23 (2H, br s), 5.11 (2H, s), 3.75(3H, s), 3.09-3.02 (2H, m), 1.01 (3H, t); MS(ESI): 513 (MH⁺).

EXAMPLE 273 Preparation ofN-{2-[3-Benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-N′,N″-di(tert-butoxycarbonyl)guanidine

To a stirred mixture of the product of Example 272 (77 mg, 0.15 mmol),N,N′-di-(tert-butoxycarbonyl)thiourea (50 mg, 0.18 mmol) and TEA (70 μL,0.5 mmol) in anhydrous DMF (1.5 mL) at 0° C. was added HgCl₂ (49 mg,0.18 mmol). The resulting mixture was stirred at 0° C. for 30 min, thenat ambient temperature overnight. The mixture was diluted with CHCl₃,washed with water and brine, dried over Na₂SO₄, and concentrated invacuo. The residue was purified by chromatography on silica gel, elutingwith MeOH-DCM (0:100 to 20:80) to afford the title compound (98 mg,87%). ¹H-NMR (CDCl₃): δ 11.62 (1H, br s), 10.43 (1H, br s), 8.02 (2H,m), 7.45-7.20 (7H, m), 7.02 (1H, d), 6.49 (1H, t), 5.16 (2H, s), 3.82(3H, s), 3.04-2.96 (2H, m), 1.43 (9H, s), 1.35 (9H, s), 1.02 (3H, t);MS(ESI): 756 (MH⁺).

EXAMPLE 274 Preparation of2-{2-[3-Benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-1,1,-dimethylurea

To the product of Example 272 (89 mg, 0.174 mmol) in anhydrous CHCl₃ (5mL) were added TEA (0.3 mL, 2.4 mmol) and dimethylcarbamyl chloride (0.2mL, 2.0 mmol). The resulting mixture was stirred at ambient temperatureovernight. After diluting with CHCl₃, the mixture was washed with satdNaHCO₃ and brine, dried over Na₂SO₄, and concentrated in vacuo. Theresidue was purified by chromatography on silica gel, eluting withMeOH-DCM (0:100 to 5:95) to afford the title compound (48 mg, 47%).¹H-NMR (CDCl₃): δ 7.70 (1H, d), 7.44-7.26 (8H, m), 7.20 (1H, d), 7.00(1H, d), 6.48 (1H, d), 6.38 (1H, s), 5.16 (2H, s), 3.79 (3H, s), 3.06(6H, s), 3.05-2.97 (2H, m), 1.02 (3H, t); MS(ESI): 584 (MH⁺).

EXAMPLE 275 A. Preparation of 5-Acetamido-2-mercaptobenzothiazole

To a stirred solution of 4-chloro-3-nitroaniline (51.8 g, 0.36 mol) inanhydrous DCM (300 mL) was added dropwise acetic anhydride (45 mL, 0.48mol) at room temperature, and the resulting solution was stirred at roomtemperature for 3 h. The solvent was removed in vacuo, and Et₂O wasadded to the residue. The precipitates were collected by filtration,washed thoroughly with Et₂O, and dried under high vacuum to give4′-chloro-3′-nitroacetanilide (78.7 g, 100%).

A mixture of Na₂S.9H₂O (65 g, 0.28 mol), sulfur (25 g, 0.78 mol) andwater (150 mL) were heated with stirring at 90° C. for 10 min, and thenpoured into a flask charged with the above 4′-chloro-3′-nitroacetanilide(21.5 g, 0.10 mol). The resulting mixture was heated at 80° C. for 10min, and then CS₂ (12 mL, 0.2 mol) was added dropwise while maintaininga gentle reflux. The resulting mixture was heated at 90° C. for 7 h. Thesolids were collected by filtration, washed with water and dilute HClsolution. The solids were taken up in water, and the solution was madealkaline with solid NaOH. The solution was filtered, and the filtratewas acidified with conc HCl. The precipitates were collected byfiltration, washed with water, and dried under high vacuum. The crudeproduct was suspended in cold water (200 mL) and solid Na₂CO₃ was addedto obtain pH 13. Dimethyl sulfate was added to the above milky solution,and the resulting mixture was stirred at ambient temperature for 3 h.The solids were collected by filtration, washed with water, and driedunder high vacuum to yield the title compound (12.4 g, 55%).

B. Preparation of 2-Methylthio-5-(2,2,2-trifluoroacetamido)benzothiazole

A suspension of 5-acetamido-2-mercaptobenzothiazole (12.9 g, 54 mmol) ina mixture of conc HCl (30 mL) and water (60 mL) was heated at reflux for3 h. After cooling, the mixture was extracted with CHCl₃, and theaqueous phase was diluted with ice-water. To the aqueous layer was addedportionwise solid NaOH to achieve pH 6, and then solid K₂CO₃ to obtainpH 8. The precipitates were collected by filtration, washed with water,and dried under high vacuum to yield 5-amino-2-methylthiobenzothiazole(7.65 g, 72%).

To a stirred solution of 5-amino-2-methylthiobenzothiazole (3.93 g, 20mmol) in anhydrous MeCN were added dropwise at 0° C. TFM (4.0 mL, 28mmol) and TEA (5 mL, 36 mmol) under N₂. The mixture was stirred at roomtemperature for 3 h. The solvent was removed in vacuo, and the residuewas taken up in EtOAc, washed with water and brine, dried with Na₂SO₄,and concentrated in vacuo. The crude material was purified bychromatography on silica gel, eluting with EtOAc-Hex (0:100 to 20:80) toafford the title, compound (3.9 g, 67%) as a pale white solid. ¹H-NMR(CDCl₃): δ 8.10 (1H, d), 7.98 (1H, br s), 7.75 (1H, d), 7.53-7.51 (1H,dd), 2.80 (3H, s).

C. Preparation ofN-{2-[3-Benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yl}-2,2,2-trifluoroacetamide

The title compound was prepared from2-methylthio-5-trifluoroacetoamido-benzothiazole in a manner similar tothat described in Example 265. ¹H-NMR (DMSO-d₆): δ 7.82 (1H, d),7.56-7.26 (8H, m), 7.16 (1H, d), 6.51 (1H, d), 5.16 (2H, s), 3.83 (3H,s), 3.03-2.96 (2H, m), 1.02 (3H, t); MS(ESI): 609 (MH⁺).

EXAMPLE 276 Preparation of3-[5-(5-Amino-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile

The title compound was prepared-from the product of Example 275 in amanner similar to that described in Example 272. ¹H-NMR (DMSO-d₆): δ8.38 (1H, s), 7.47-7.36 (6H, m), 7.21 (1H, d), 6.69 (1H, d), 6.61-6.56(2H, m), 4.45 (2H, br s), 5.18 (2H, s), 3.78 (3H, s), 3.12 (2H, m), 1.06(3H, t) MS(ESI): 513 (MH⁺).

EXAMPLE 277 Preparation of{2-[3-Benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}carbamicAcid Ethyl Ester

The title compound was prepared in a manner similar to that described inExample 274 by replacing dimethylcarbamyl chloride with ethylchoroformate. ¹H-NMR (DMSO-d₆): δ 9.64 (1H, s), 7.75 (1H, d), 7.29-7.16(8H, m), 7.02 (1H, d), 6.51 (1H, d), 5.00 (2H, s), 4.04-3.98 (2H, q),3.68 (3H, s), 2.97-2.91 (2H, m), 1.26 (3H, t), 0.88 (3H, t); MS(ESI):585 (MH⁺).

EXAMPLE 278 Preparation ofN-[2-(3-Benzyl-2-{5-cyano-2-[ethyl-2-morpholin-ylethyl)amino]phenylimino}-4-oxothiazilidin-5-ylidene)-3-methyl-2,3-dihydrobenzothiazol-6-yl]-2,2,2-trifluoroacetamide

Sodium hydride (8 mg, 60% w/w in mineral oil, 0.2 mmol) was added at 0°C. to a stirred solution of the product of Example 271 (52 mg, 0.1 mmol)in anhydrous DMF under N₂. The mixture was stirred at 0° C. for 5 min,then at ambient temperature for 15 min. 4-(2-Chloroethyl)morpholinehydrochloride 24 mg, 0.15 mmol) was added to the above red solution at0° C., and the mixture was stirred at ambient temperature under N₂ for21 h. The reaction mixture was diluted with CHCl₃, washed thoroughlywith water, dried over Na₂SO₄, and concentrated under reduced pressure.The residue was purified by chromatography on silica gel, eluting withMeOH-DCM (0:100 to 20:80) to afford the title compound (42 mg, 58%) as ayellow solid. ¹H-NMR (CDCl₃): δ 8.98 (1H, br s), 7.92 (1H, s), 7.68 (1H,s), 7.51-7.22 (7H, m), 6.81 (1H, d), 5.12 (2H, s), 4.04 (2H, m), 3.64(5H, m), 3.36 (2H, m), 2.54-2.17 (8H, m), 1.26 (3H, m); MS(ESI): 722(MH⁺).

EXAMPLE 279 Preparation ofN-{2-[3-Benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-2,2,2-trifluoro-N-(2-morpholin-4ylethyl)acetamide

To the product of Example 271 (65 mg, 0.11 mmol) in anhydrous DMF wereadded 4-(2-chloroethyl)morpholine hydrochloride (50 mg, 0.3 mmol), K₂CO₃(30 mg, 0.21 mmol) and KI (10 mg). The reaction mixture was heated at90° C. for 30 h, cooled, and diluted with CHCl₃. The solution was washedwith water, dried over Na₂SO₄, and concentrated in vacuo. The crudematerial was purified by chromatography on silica gel, eluting withMeOH-DCM (0:100 to 20:80) to afford the title compound (72 mg, 94%) as ayellow solid. ¹H-NMR (CDCl₃): δ 7.51 (1H, s), 7.44-7.42 (2H, m),7.38-7.28 (5H, m), 7.19 (1H, d), 7.09 (1H, d), 5.18 (2H, s), 4.21 (2H,br s), 3.85 (3H, s), 3.68 (4H, br s), 3.05-2.96 (2H, m), 2.52-2.45 (6H,m), 1.03 (3H, t); MS(ESI): 722 (MH⁺).

EXAMPLE 280 Preparation of3-{3-Benzyl-5-[3-methyl-6-(2-morpholin-4-yl-ethylamino)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared from the product of Example 279 in amanner similar to that described in Example 272. ¹H-NMR (CDCl₃): δ7.44-7.21 (7H, m), 6.93 (1H, d), 6.78 (1H, d), 6.65 (1H, m), 6.48 (1H,d), 5.17 (2H, s), 3.81 (3H, s), 3.80-3.74 (4H, m), 3.20-3.17 (2H, m),3.03-2.96 (2H, m), 2.67 (2H, br s), 2.49 (4H, br s), 1.02 (3H, t);MS(ESI): 626 (MH⁺).

EXAMPLE 281 Preparation of3-{3-Benzyl-5-[3-methyl-6-(2-piperidin-1-yl-ethylamino)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExamples 279 and 280 by replacing 4-(2-chloroethyl)morpholinehydrochloride with 4-(2-chloroethyl)piperidine hydrochloride. ¹H-NMR(CDCl₃): δ 7.44-7.19 (7H, m), 6.93 (1H, d), 6.77-6.71 (2H, m), 6.48 (1H,d), 5.16 (2H, s), 3.77 (3H, s), 3.28 (2H, br s), 3.03-2.96 (2H, m), 2.81(2H, br s), 2.48 (2H, br s), 2.04 (4H, br s), 1.02 (3H, t); MS(ESI): 624(MH⁺).

EXAMPLE 282 Preparation ofN-{2-[3-Benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yl}-2,2,2-trifluoro-N-(2-morpholin-4ylethyl)acetamide

The title compound was prepared from the product of Example 275 in amanner similar to that described in Example 279. ¹H-NMR (CDCl₃): δ 7.54(1H, d), 7.44-7.11 (9H, m), 6.50 (1H, d), 5.18 (2H, s), 3.95 (2H, m),3.79 (3H, s), 3.70 (4H, m), 3.04-2.98 (2H, m), 2.49 (6H, m), 1.03 (3H,t); MS(ESI): 722 (MH⁺).

EXAMPLE 283 Preparation of3-{3-Benzyl-5-[3-methyl-5-(2-morpholin-4-yl-ethylamino)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared from the product of Example 282 in amanner similar to that described in Example 272. ¹H-NMR (CDCl₃): δ 7.54(1H, d), 7.44-7.11 (9H, m), 6.50 (1H, d), 5.18 (2H, s), 3.80 (2H, s),3.70 (4H, br s), 3.04-2.98 (2H, m), 2.49 (6H, br s), 1.03 (3H, t);MS(ESI): 626 (MH⁺).

EXAMPLE 284 Preparation ofN-{2-[3-Benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}guanidine

To a stirred solution of the product of Example 273 (116 mg, 0.15 mmol)in anhydrous DCM (6 mL) was added TFA (3 mL) at 0° C. The reactionmixture was stirred at 0° C. for 30 min, then at ambient temperature for14 h. The solvent was removed in vacuo, and the residue was purified byreverse-phase HPLC (C18 column), eluting with 0.05% TFA in MeCN—H₂O (1:9to 9:1) to afford the title compound (25 mg, 30%) as a yellow solid.¹H-NMR (DMSO-d₆): δ 9.65 (1H, s), 7.72 (1H, d), 7.48 (1H, d), 7.41-7.25(8H, m), 7.15 (1H, d), 6.65 (1H, d), 5.14 (2H, s), 3.84 (3H, s), 3.07(2H, m), 1.01 (3H, t); MS(ESI): 555 (MH⁺).

EXAMPLE 285 Preparation of3-{3-Benzyl-5-[3-methyl-6-(4-trifluoromethylbenzylamino)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile

The title compound was prepared in a manner similar to that described inExamples 279 and 280 by replacing 4-(2-chloroethyl)morpholinehydrochloride with 4-(trifluoromethyl)benzyl bromide. ¹H-NMR (DMSO-d₆):δ 7.69 (2H, d), 7.58 (2H, d), 7.38-7.32 (6H, m), 7.17 (1H, d), 7.14 (1H,d), 6.94 (1H, d), 6.63 (1H, dd), 6.61 (1H, d), 5.10 (2H, s), 4.40 (2H,s), 3.73 (3H, s), 3.05 (2H, m), 1.00 (3H, t); MS(ESI): 671 (MH⁺).

EXAMPLE 286 Preparation ofN-{2-[3-Benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-N-(3-fluoropropyl)-2,2,2-trifluoroacetamide

The title compound was prepared in a manner similar to that described inExample 279 by replacing 4-(2-chloroethyl)morpholine hydrochloride with1-bromo-3-fluoropropane. ¹H-NMR (CDCl₃): δ 7.44-7.19 (9H, m), 7.10 (1H,d), 6.50 (1H, d), 5.18 (2H, s), 4.60 (1H, m), 4.48 (1H, m), 4.20 (1H,m), 3.91 (1H, m), 3.83 (3H, s), 3.01 (2H, m), 2.09-1.99 (2H, m), 1.03(3H, t); MS(ESI): 669 (MH⁺).

EXAMPLE 287 Preparation ofN-{2-[3-Benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-N-(3-cyanopropyl)-2,2,2-trifluoroacetamide

The title compound was prepared in a manner similar to that described inExample 279 by replacing 4-(2-chloroethyl)morpholine hydrochloride with4-bromobutyronitrile. ¹H-NMR (CDCl₃): δ 7.44-7.19 (9H, m), 7.11 91H, d),6.51 91H, d), 5.19 (2H, s), 3.86 (3H, s), 3.85-3.77 (2H, m), 3.05-2.98(2H, m), 2.53-2.44 (2H, m), 2.04-1.88 (2H, m), 1.03 (3H, t); MS(ESI):676 (MH⁺).

EXAMPLE 288 Preparation of3-{3-Benzyl-5-[6-(3-cyanopropylamino)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-(ethylamino)benzonitrile

The title compound was prepared from the product of Example 287 in amanner similar to that described in Example 272. ¹H-NMR (CDCl₃): δ7.44-7.20 (7H, m), 6.94 (1H, d), 6.77 (1H, d), 6.65 (1H, dd), 6.48 (1H,d), 5.17 (2H, s), 3.77 (3H, s), 3.34 (2H, m), 3.01 (2H, m), 2.49 (2H,m), 2.01 (2H, m), 1.02 (3H, t); MS(ESI): 580 (MH⁺).

EXAMPLE 289 Preparation of3-{3-Benzyl-5-[6-(3-hydroxypropylamino)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-(ethylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExamples 279 and 280 by replacing 4-(2-chloroethyl)morpholinehydrochloride with 3-bromopropanol. ¹H-NMR (CDCl₃): δ 7.44-7.21 (8H, m),6.93 (1H, d), 6.79 (1H, d), 6.65 (1H, dd), 6.48 (1H, d), 5.17 (2H, s),3.85 (2H, m), 3.77 (3H, s), 3.30 (2H, t), 3.01 (2H, m), 1.92 (2H, m),1.02 (3H, t); MS(ESI): 571 (MH⁺).

EXAMPLE 290 Preparation of3-{3-Benzyl-5-[6-(2-methoxyethylamino)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}4-(ethylamino)benzonitrile

The title compound was prepared in a manner similar to that described inExamples 279 and 280 by replacing 4-(2-chloroethyl)morpholinehydrochloride with 2-bromoethyl methyl ether. ¹H-NMR (CDCl₃): δ7.44-7.21 (7H, m), 6.93 (1H, d), 6.79 (1H, d), 6.66 (1H, dd), 6.48 (1H,d), 5.17 (2H, s), 3.77 (3H, s), 3.63 (2H, m), 3.41 (3H, s), 3.30 (2H,m), 3.00 (2H, m), 1.02 (3H, t); MS(ESI): 571 (MH⁺).

EXAMPLE 291

In Vivo Studies

In order to evaluate direct regulation of key target genes by thecompounds of the invention, animals are administered a single oral doseof the test compound and tissues collected at six or fifteen hours afterdose. Male C57BL/6 mice (n=8) are dosed by oral gavage with vehicle orcompound. At six and fifteen hours after the dose, animals are bled viathe retro orbital sinus for plasma collection. Animals are theneuthanized and tissues, such as liver and intestinal mucosa arecollected and snap frozen for further analysis. Plasma is analyzed forlipid parameters, such as total cholesterol, HDL cholesterol andtriglyceride levels. RNA is extracted for frozen tissues and can beanalyzed by quantitative real time PCR for regulation of key targetgenes. To identify specificity of target gene regulation by FXR, knockout mice (FXR^(−/−)) and C57BL/6 wild-type controls maybe used in thissame protocol.

Plasma Lipid Evaluation

To compare the effects of compounds on plasma cholesterol andtriglycerides, animals are dosed with compound for one week and plasmalipid levels are monitored throughout the study. Male C57BL/6 mice (n=8)are dosed daily by oral gavage with vehicle or compound. Plasma samplesare taken on day-1 (in order to group animals), day 1, 3, and 7. Samplesare collected three hours after the daily dose. On day 7 of the study,following plasma collection, animals are euthanized and tissues, such asliver and intestinal mucosa are collected and snap frozen for furtheranalysis. Plasma is analyzed for lipid parameters, such as totalcholesterol, HDL cholesterol and triglyceride levels. RNA is extractedfor frozen tissues and can be analyzed by quantitative real time PCR forregulation of key target genes. To identify specificity of target generegulation by FXR knockout mice and C57BL/6 wild-type controls maybeused in this same protocol.

Cholesterol Absorption

Evaluation of compounds to inhibit cholesterol absorption is done viameasurement of labeled cholesterol in feces. Male A129 mice (n=7) aredosed daily by oral gavage with vehicle or compound for 7 days. On day 7of the study, animals are administered [¹⁴C]-cholesterol and[³H]-sitostanol by oral gavage. Animals are individually housed on wireracks for the next 24 hours in order to collect feces. Feces are thendried and ground to a fine powder. Labeled cholesterol and sitostanolare extracted from the feces and ratios of the two are counted on aliquid scintillation counter in order to evaluate the amount ofcholesterol absorbed by the individual animal.

Since modifications will be apparent to those of skill in this art, itis intended that the subject matter claimed herein be limited only bythe scope of the appended claims.

18 1 1528 DNA Homo Sapien CDS (36)...(1379) GeneBank Nm_0056932002-05-14 1 cagtgccttg gtaatgacca gggctccaga aagag atg tcc ttg tgg ctgggg 53 Met Ser Leu Trp Leu Gly 1 5 gcc cct gtg cct gac att cct cct gactct gcg gtg gag ctg tgg aag 101 Ala Pro Val Pro Asp Ile Pro Pro Asp SerAla Val Glu Leu Trp Lys 10 15 20 cca ggc gca cag gat gca agc agc cag gcccag gga ggc agc agc tgc 149 Pro Gly Ala Gln Asp Ala Ser Ser Gln Ala GlnGly Gly Ser Ser Cys 25 30 35 atc ctc aga gag gaa gcc agg atg ccc cac tctgct ggg ggt act gca 197 Ile Leu Arg Glu Glu Ala Arg Met Pro His Ser AlaGly Gly Thr Ala 40 45 50 ggg gtg ggg ctg gag gct gca gag ccc aca gcc ctgctc acc agg gca 245 Gly Val Gly Leu Glu Ala Ala Glu Pro Thr Ala Leu LeuThr Arg Ala 55 60 65 70 gag ccc cct tca gaa ccc aca gag atc cgt cca caaaag cgg aaa aag 293 Glu Pro Pro Ser Glu Pro Thr Glu Ile Arg Pro Gln LysArg Lys Lys 75 80 85 ggg cca gcc ccc aaa atg ctg ggg aac gag cta tgc agcgtg tgt ggg 341 Gly Pro Ala Pro Lys Met Leu Gly Asn Glu Leu Cys Ser ValCys Gly 90 95 100 gac aag gcc tcg ggc ttc cac tac aat gtt ctg agc tgcgag ggc tgc 389 Asp Lys Ala Ser Gly Phe His Tyr Asn Val Leu Ser Cys GluGly Cys 105 110 115 aag gga ttc ttc cgc cgc agc gtc atc aag gga gcg cactac atc tgc 437 Lys Gly Phe Phe Arg Arg Ser Val Ile Lys Gly Ala His TyrIle Cys 120 125 130 cac agt ggc ggc cac tgc ccc atg gac acc tac atg cgtcgc aag tgc 485 His Ser Gly Gly His Cys Pro Met Asp Thr Tyr Met Arg ArgLys Cys 135 140 145 150 cag gag tgt cgg ctt cgc aaa tgc cgt cag gct ggcatg cgg gag gag 533 Gln Glu Cys Arg Leu Arg Lys Cys Arg Gln Ala Gly MetArg Glu Glu 155 160 165 tgt gtc ctg tca gaa gaa cag atc cgc ctg aag aaactg aag cgg caa 581 Cys Val Leu Ser Glu Glu Gln Ile Arg Leu Lys Lys LeuLys Arg Gln 170 175 180 gag gag gaa cag gct cat gcc aca tcc ttg ccc cccagg cgt tcc tca 629 Glu Glu Glu Gln Ala His Ala Thr Ser Leu Pro Pro ArgArg Ser Ser 185 190 195 ccc ccc caa atc ctg ccc cag ctc agc ccg gaa caactg ggc atg atc 677 Pro Pro Gln Ile Leu Pro Gln Leu Ser Pro Glu Gln LeuGly Met Ile 200 205 210 gag aag ctc gtc gct gcc cag caa cag tgt aac cggcgc tcc ttt tct 725 Glu Lys Leu Val Ala Ala Gln Gln Gln Cys Asn Arg ArgSer Phe Ser 215 220 225 230 gac cgg ctt cga gtc acg cct tgg ccc atg gcacca gat ccc cat agc 773 Asp Arg Leu Arg Val Thr Pro Trp Pro Met Ala ProAsp Pro His Ser 235 240 245 cgg gag gcc cgt cag cag cgc ttt gcc cac ttcact gag ctg gcc atc 821 Arg Glu Ala Arg Gln Gln Arg Phe Ala His Phe ThrGlu Leu Ala Ile 250 255 260 gtc tct gtg cag gag ata gtt gac ttt gct aaacag cta ccc ggc ttc 869 Val Ser Val Gln Glu Ile Val Asp Phe Ala Lys GlnLeu Pro Gly Phe 265 270 275 ctg cag ctc agc cgg gag gac cag att gcc ctgctg aag acc tct gcg 917 Leu Gln Leu Ser Arg Glu Asp Gln Ile Ala Leu LeuLys Thr Ser Ala 280 285 290 atc gag gtg atg ctt ctg gag aca tct cgg aggtac aac cct ggg agt 965 Ile Glu Val Met Leu Leu Glu Thr Ser Arg Arg TyrAsn Pro Gly Ser 295 300 305 310 gag agt atc acc ttc ctc aag gat ttc agttat aac cgg gaa gac ttt 1013 Glu Ser Ile Thr Phe Leu Lys Asp Phe Ser TyrAsn Arg Glu Asp Phe 315 320 325 gcc aaa gca ggg ctg caa gtg gaa ttc atcaac ccc atc ttc gag ttc 1061 Ala Lys Ala Gly Leu Gln Val Glu Phe Ile AsnPro Ile Phe Glu Phe 330 335 340 tcc agg gcc atg aat gag ctg caa ctc aatgat gcc gag ttt gcc ttg 1109 Ser Arg Ala Met Asn Glu Leu Gln Leu Asn AspAla Glu Phe Ala Leu 345 350 355 ctc att gct atc agc atc ttc tct gca gaccgg ccc aac gtg cag gac 1157 Leu Ile Ala Ile Ser Ile Phe Ser Ala Asp ArgPro Asn Val Gln Asp 360 365 370 cag ctc cag gtg gag agg ctg cag cac acatat gtg gaa gcc ctg cat 1205 Gln Leu Gln Val Glu Arg Leu Gln His Thr TyrVal Glu Ala Leu His 375 380 385 390 gcc tac gtc tcc atc cac cat ccc catgac cga ctg atg ttc cca cgg 1253 Ala Tyr Val Ser Ile His His Pro His AspArg Leu Met Phe Pro Arg 395 400 405 atg cta atg aaa ctg gtg agc ctc cggacc ctg agc agc gtc cac tca 1301 Met Leu Met Lys Leu Val Ser Leu Arg ThrLeu Ser Ser Val His Ser 410 415 420 gag caa gtg ttt gca ctg cgt ctg caggac aaa aag ctc cca ccg ctg 1349 Glu Gln Val Phe Ala Leu Arg Leu Gln AspLys Lys Leu Pro Pro Leu 425 430 435 ctc tct gag atc tgg gat gtg cac gaatga ctgttctgtc cccatatttt 1399 Leu Ser Glu Ile Trp Asp Val His Glu * 440445 ctgttttctt ggccggatgg ctgaggcctg gtggctgcct cctagaagtg gaacagactg1459 agaagggcaa acattcctgg gagctgggca aggagatcct cccgtggcat taaaagagag1519 tcaaagggt 1528 2 447 PRT Homo Sapien 2 Met Ser Leu Trp Leu Gly AlaPro Val Pro Asp Ile Pro Pro Asp Ser 1 5 10 15 Ala Val Glu Leu Trp LysPro Gly Ala Gln Asp Ala Ser Ser Gln Ala 20 25 30 Gln Gly Gly Ser Ser CysIle Leu Arg Glu Glu Ala Arg Met Pro His 35 40 45 Ser Ala Gly Gly Thr AlaGly Val Gly Leu Glu Ala Ala Glu Pro Thr 50 55 60 Ala Leu Leu Thr Arg AlaGlu Pro Pro Ser Glu Pro Thr Glu Ile Arg 65 70 75 80 Pro Gln Lys Arg LysLys Gly Pro Ala Pro Lys Met Leu Gly Asn Glu 85 90 95 Leu Cys Ser Val CysGly Asp Lys Ala Ser Gly Phe His Tyr Asn Val 100 105 110 Leu Ser Cys GluGly Cys Lys Gly Phe Phe Arg Arg Ser Val Ile Lys 115 120 125 Gly Ala HisTyr Ile Cys His Ser Gly Gly His Cys Pro Met Asp Thr 130 135 140 Tyr MetArg Arg Lys Cys Gln Glu Cys Arg Leu Arg Lys Cys Arg Gln 145 150 155 160Ala Gly Met Arg Glu Glu Cys Val Leu Ser Glu Glu Gln Ile Arg Leu 165 170175 Lys Lys Leu Lys Arg Gln Glu Glu Glu Gln Ala His Ala Thr Ser Leu 180185 190 Pro Pro Arg Arg Ser Ser Pro Pro Gln Ile Leu Pro Gln Leu Ser Pro195 200 205 Glu Gln Leu Gly Met Ile Glu Lys Leu Val Ala Ala Gln Gln GlnCys 210 215 220 Asn Arg Arg Ser Phe Ser Asp Arg Leu Arg Val Thr Pro TrpPro Met 225 230 235 240 Ala Pro Asp Pro His Ser Arg Glu Ala Arg Gln GlnArg Phe Ala His 245 250 255 Phe Thr Glu Leu Ala Ile Val Ser Val Gln GluIle Val Asp Phe Ala 260 265 270 Lys Gln Leu Pro Gly Phe Leu Gln Leu SerArg Glu Asp Gln Ile Ala 275 280 285 Leu Leu Lys Thr Ser Ala Ile Glu ValMet Leu Leu Glu Thr Ser Arg 290 295 300 Arg Tyr Asn Pro Gly Ser Glu SerIle Thr Phe Leu Lys Asp Phe Ser 305 310 315 320 Tyr Asn Arg Glu Asp PheAla Lys Ala Gly Leu Gln Val Glu Phe Ile 325 330 335 Asn Pro Ile Phe GluPhe Ser Arg Ala Met Asn Glu Leu Gln Leu Asn 340 345 350 Asp Ala Glu PheAla Leu Leu Ile Ala Ile Ser Ile Phe Ser Ala Asp 355 360 365 Arg Pro AsnVal Gln Asp Gln Leu Gln Val Glu Arg Leu Gln His Thr 370 375 380 Tyr ValGlu Ala Leu His Ala Tyr Val Ser Ile His His Pro His Asp 385 390 395 400Arg Leu Met Phe Pro Arg Met Leu Met Lys Leu Val Ser Leu Arg Thr 405 410415 Leu Ser Ser Val His Ser Glu Gln Val Phe Ala Leu Arg Leu Gln Asp 420425 430 Lys Lys Leu Pro Pro Leu Leu Ser Glu Ile Trp Asp Val His Glu 435440 445 3 1815 DNA Homo Sapien CDS (56)...(1438) GeneBank XM_0464192002-08-01 3 cgctgttgct tggagagggg cgggacctgg agagaggctg ctccgtgaccccacc atg 58 Met 1 tcc tct cct acc acg agt tcc ctg gat acc ccc ctg cctgga aat ggc 106 Ser Ser Pro Thr Thr Ser Ser Leu Asp Thr Pro Leu Pro GlyAsn Gly 5 10 15 ccc cct cag cct ggc gcc cct tct tct tca ccc act gta aaggag gag 154 Pro Pro Gln Pro Gly Ala Pro Ser Ser Ser Pro Thr Val Lys GluGlu 20 25 30 ggt ccg gag ccg tgg ccc ggg ggt ccg gac cct gat gtc cca ggcact 202 Gly Pro Glu Pro Trp Pro Gly Gly Pro Asp Pro Asp Val Pro Gly Thr35 40 45 gat gag gcc agc tca gcc tgc agc aca gac tgg gtc atc cca gat ccc250 Asp Glu Ala Ser Ser Ala Cys Ser Thr Asp Trp Val Ile Pro Asp Pro 5055 60 65 gaa gag gaa cca gag cgc aag cga aag aag ggc cca gcc ccg aag atg298 Glu Glu Glu Pro Glu Arg Lys Arg Lys Lys Gly Pro Ala Pro Lys Met 7075 80 ctg ggc cac gag ctt tgc cgt gtc tgt ggg gac aag gcc tcc ggc ttc346 Leu Gly His Glu Leu Cys Arg Val Cys Gly Asp Lys Ala Ser Gly Phe 8590 95 cac tac aac gtg ctc agc tgc gaa ggc tgc aag ggc ttc ttc cgg cgc394 His Tyr Asn Val Leu Ser Cys Glu Gly Cys Lys Gly Phe Phe Arg Arg 100105 110 agt gtg gtc cgt ggt ggg gcc agg cgc tat gcc tgc cgg ggt ggc gga442 Ser Val Val Arg Gly Gly Ala Arg Arg Tyr Ala Cys Arg Gly Gly Gly 115120 125 acc tgc cag atg gac gct ttc atg cgg cgc aag tgc cag cag tgc cgg490 Thr Cys Gln Met Asp Ala Phe Met Arg Arg Lys Cys Gln Gln Cys Arg 130135 140 145 ctg cgc aag tgc aag gag gca ggg atg agg gag cag tgc gtc ctttct 538 Leu Arg Lys Cys Lys Glu Ala Gly Met Arg Glu Gln Cys Val Leu Ser150 155 160 gaa gaa cag atc cgg aag aag aag att cgg aaa cag cag cag gagtca 586 Glu Glu Gln Ile Arg Lys Lys Lys Ile Arg Lys Gln Gln Gln Glu Ser165 170 175 cag tca cag tcg cag tca cct gtg ggg ccg cag ggc agc agc agctca 634 Gln Ser Gln Ser Gln Ser Pro Val Gly Pro Gln Gly Ser Ser Ser Ser180 185 190 gcc tct ggg cct ggg gct tcc cct ggt gga tct gag gca ggc agccag 682 Ala Ser Gly Pro Gly Ala Ser Pro Gly Gly Ser Glu Ala Gly Ser Gln195 200 205 ggc tcc ggg gaa ggc gag ggt gtc cag cta aca gcg gct caa gaacta 730 Gly Ser Gly Glu Gly Glu Gly Val Gln Leu Thr Ala Ala Gln Glu Leu210 215 220 225 atg atc cag cag ttg gtg gcg gcc caa ctg cag tgc aac aaacgc tcc 778 Met Ile Gln Gln Leu Val Ala Ala Gln Leu Gln Cys Asn Lys ArgSer 230 235 240 ttc tcc gac cag ccc aaa gtc acg ccc tgg ccc ctg ggc gcagac ccc 826 Phe Ser Asp Gln Pro Lys Val Thr Pro Trp Pro Leu Gly Ala AspPro 245 250 255 cag tcc cga gat gcc cgc cag caa cgc ttt gcc cac ttc acggag ctg 874 Gln Ser Arg Asp Ala Arg Gln Gln Arg Phe Ala His Phe Thr GluLeu 260 265 270 gcc atc atc tca gtc cag gag atc gtg gac ttc gct aag caagtg cct 922 Ala Ile Ile Ser Val Gln Glu Ile Val Asp Phe Ala Lys Gln ValPro 275 280 285 ggt ttc ctg cag ctg ggc cgg gag gac cag atc gcc ctc ctgaag gca 970 Gly Phe Leu Gln Leu Gly Arg Glu Asp Gln Ile Ala Leu Leu LysAla 290 295 300 305 tcc act atc gag atc atg ctg cta gag aca gcc agg cgctac aac cac 1018 Ser Thr Ile Glu Ile Met Leu Leu Glu Thr Ala Arg Arg TyrAsn His 310 315 320 gag aca gag tgt atc acc ttc ttg aag gac ttc acc tacagc aag gac 1066 Glu Thr Glu Cys Ile Thr Phe Leu Lys Asp Phe Thr Tyr SerLys Asp 325 330 335 gac ttc cac cgt gca ggc ctg cag gtg gag ttc atc aacccc atc ttc 1114 Asp Phe His Arg Ala Gly Leu Gln Val Glu Phe Ile Asn ProIle Phe 340 345 350 gag ttc tcg cgg gcc atg cgg cgg ctg ggc ctg gac gacgct gag tac 1162 Glu Phe Ser Arg Ala Met Arg Arg Leu Gly Leu Asp Asp AlaGlu Tyr 355 360 365 gcc ctg ctc atc gcc atc aac atc ttc tcg gcc gac cggccc aac gtg 1210 Ala Leu Leu Ile Ala Ile Asn Ile Phe Ser Ala Asp Arg ProAsn Val 370 375 380 385 cag gag ccg ggc cgc gtg gag gcg ttg cag cag ccctac gtg gag gcg 1258 Gln Glu Pro Gly Arg Val Glu Ala Leu Gln Gln Pro TyrVal Glu Ala 390 395 400 ctg ctg tcc tac acg cgc atc aag agg ccg cag gaccag ctg cgc ttc 1306 Leu Leu Ser Tyr Thr Arg Ile Lys Arg Pro Gln Asp GlnLeu Arg Phe 405 410 415 ccg cgc atg ctc atg aag ctg gtg agc ctg cgc acgctg agc tct gtg 1354 Pro Arg Met Leu Met Lys Leu Val Ser Leu Arg Thr LeuSer Ser Val 420 425 430 cac tcg gag cag gtc ttc gcc ttg cgg ctc cag gacaag aag ctg ccg 1402 His Ser Glu Gln Val Phe Ala Leu Arg Leu Gln Asp LysLys Leu Pro 435 440 445 cct ctg ctg tcg gag atc tgg gac gtc cac gag tgaggggctggcc 1448 Pro Leu Leu Ser Glu Ile Trp Asp Val His Glu * 450 455460 acccagcccc acagccttgc ctgaccaccc tccagcagat agacgccggc accccttcct1508 cttcctaggg tggaaggggc cctgggccga gcctgtagac ctatcggctc tcatcccttg1568 ggataagccc cagtccaggt ccaggaggct ccctccctgc ccagcgagtc ttccagaagg1628 ggtgaaaggg ttgcaggtcc cgaccactga cccttcccgg ctgccctccc tccccagctt1688 acacctcaag cccagcacgc agtgcacctt gaacagaggg aggggaggac ccatggctct1748 cccccctagc ccgggagacc agggccttcc tcttcctctg cttttattta ataaaaacta1808 aaaacag 1815 4 460 PRT Homo Sapien 4 Met Ser Ser Pro Thr Thr SerSer Leu Asp Thr Pro Leu Pro Gly Asn 1 5 10 15 Gly Pro Pro Gln Pro GlyAla Pro Ser Ser Ser Pro Thr Val Lys Glu 20 25 30 Glu Gly Pro Glu Pro TrpPro Gly Gly Pro Asp Pro Asp Val Pro Gly 35 40 45 Thr Asp Glu Ala Ser SerAla Cys Ser Thr Asp Trp Val Ile Pro Asp 50 55 60 Pro Glu Glu Glu Pro GluArg Lys Arg Lys Lys Gly Pro Ala Pro Lys 65 70 75 80 Met Leu Gly His GluLeu Cys Arg Val Cys Gly Asp Lys Ala Ser Gly 85 90 95 Phe His Tyr Asn ValLeu Ser Cys Glu Gly Cys Lys Gly Phe Phe Arg 100 105 110 Arg Ser Val ValArg Gly Gly Ala Arg Arg Tyr Ala Cys Arg Gly Gly 115 120 125 Gly Thr CysGln Met Asp Ala Phe Met Arg Arg Lys Cys Gln Gln Cys 130 135 140 Arg LeuArg Lys Cys Lys Glu Ala Gly Met Arg Glu Gln Cys Val Leu 145 150 155 160Ser Glu Glu Gln Ile Arg Lys Lys Lys Ile Arg Lys Gln Gln Gln Glu 165 170175 Ser Gln Ser Gln Ser Gln Ser Pro Val Gly Pro Gln Gly Ser Ser Ser 180185 190 Ser Ala Ser Gly Pro Gly Ala Ser Pro Gly Gly Ser Glu Ala Gly Ser195 200 205 Gln Gly Ser Gly Glu Gly Glu Gly Val Gln Leu Thr Ala Ala GlnGlu 210 215 220 Leu Met Ile Gln Gln Leu Val Ala Ala Gln Leu Gln Cys AsnLys Arg 225 230 235 240 Ser Phe Ser Asp Gln Pro Lys Val Thr Pro Trp ProLeu Gly Ala Asp 245 250 255 Pro Gln Ser Arg Asp Ala Arg Gln Gln Arg PheAla His Phe Thr Glu 260 265 270 Leu Ala Ile Ile Ser Val Gln Glu Ile ValAsp Phe Ala Lys Gln Val 275 280 285 Pro Gly Phe Leu Gln Leu Gly Arg GluAsp Gln Ile Ala Leu Leu Lys 290 295 300 Ala Ser Thr Ile Glu Ile Met LeuLeu Glu Thr Ala Arg Arg Tyr Asn 305 310 315 320 His Glu Thr Glu Cys IleThr Phe Leu Lys Asp Phe Thr Tyr Ser Lys 325 330 335 Asp Asp Phe His ArgAla Gly Leu Gln Val Glu Phe Ile Asn Pro Ile 340 345 350 Phe Glu Phe SerArg Ala Met Arg Arg Leu Gly Leu Asp Asp Ala Glu 355 360 365 Tyr Ala LeuLeu Ile Ala Ile Asn Ile Phe Ser Ala Asp Arg Pro Asn 370 375 380 Val GlnGlu Pro Gly Arg Val Glu Ala Leu Gln Gln Pro Tyr Val Glu 385 390 395 400Ala Leu Leu Ser Tyr Thr Arg Ile Lys Arg Pro Gln Asp Gln Leu Arg 405 410415 Phe Pro Arg Met Leu Met Lys Leu Val Ser Leu Arg Thr Leu Ser Ser 420425 430 Val His Ser Glu Gln Val Phe Ala Leu Arg Leu Gln Asp Lys Lys Leu435 440 445 Pro Pro Leu Leu Ser Glu Ile Trp Asp Val His Glu 450 455 4605 2070 DNA Rattus norvegicus CDS (172)...(1581) GeneBank U183741995-06-21 5 ctgagttctg agcgtctaca gcgaaagtgc tgggctttgg aaaggagacctgggctccga 60 atcctctcag ggccttggac gtctctgacc caaaacaatc caaggttcttatttgaagac 120 caccatccca gaagcacatt ctcgagttga aaagttggag tggtgttcga aatg aat 177 Met Asn 1 ctg att ggg ccc tcc cat tta caa gcc acg gac gagttt gct ctt tct 225 Leu Ile Gly Pro Ser His Leu Gln Ala Thr Asp Glu PheAla Leu Ser 5 10 15 gaa aac tta ttt gga gtg cta aca gag cac gcg gca ggtcct ctg ggg 273 Glu Asn Leu Phe Gly Val Leu Thr Glu His Ala Ala Gly ProLeu Gly 20 25 30 cag aat ctg gac ttg gaa tcg tac tcc cca tac aac aat gtgcag ttt 321 Gln Asn Leu Asp Leu Glu Ser Tyr Ser Pro Tyr Asn Asn Val GlnPhe 35 40 45 50 cct caa gtt cag cca cag atc tcc tcc tcg tcc tat tat tccaac ctg 369 Pro Gln Val Gln Pro Gln Ile Ser Ser Ser Ser Tyr Tyr Ser AsnLeu 55 60 65 ggt ttc tac ccg caa caa ccg gaa gac tgg tac tct cct gga ctctat 417 Gly Phe Tyr Pro Gln Gln Pro Glu Asp Trp Tyr Ser Pro Gly Leu Tyr70 75 80 gaa ctc agg cga atg ccc act gag agt gtg tac cag gga gag act gag465 Glu Leu Arg Arg Met Pro Thr Glu Ser Val Tyr Gln Gly Glu Thr Glu 8590 95 gta tcc gag atg cct gtg aca aag aag ccg cga atg gcc gcc tca tcg513 Val Ser Glu Met Pro Val Thr Lys Lys Pro Arg Met Ala Ala Ser Ser 100105 110 gcg gga aga ata aaa ggg gat gag ctg tgt gtg gtc tgc gga gac agg561 Ala Gly Arg Ile Lys Gly Asp Glu Leu Cys Val Val Cys Gly Asp Arg 115120 125 130 gcc tct ggg tac cat tac aac gcg ctc acc tgc gag ggc tgc aaaggt 609 Ala Ser Gly Tyr His Tyr Asn Ala Leu Thr Cys Glu Gly Cys Lys Gly135 140 145 ttc ttc cga aga agc atc acc aaa aac gcc gtg tac aag tgt aagaac 657 Phe Phe Arg Arg Ser Ile Thr Lys Asn Ala Val Tyr Lys Cys Lys Asn150 155 160 ggg ggc aac tgc gtg atg gat atg tac atg cgt cgg aag tgc caggat 705 Gly Gly Asn Cys Val Met Asp Met Tyr Met Arg Arg Lys Cys Gln Asp165 170 175 tgc cgg cta agg aag tgc aga gag atg gga atg ttg gct gaa tgtttg 753 Cys Arg Leu Arg Lys Cys Arg Glu Met Gly Met Leu Ala Glu Cys Leu180 185 190 tta act gaa att cag tgt aaa tct aaa cgg cta agg aaa aat gtgaag 801 Leu Thr Glu Ile Gln Cys Lys Ser Lys Arg Leu Arg Lys Asn Val Lys195 200 205 210 cag cat gcg gat cag aca gtg aat gag gac agc gaa ggg cgtgac ttg 849 Gln His Ala Asp Gln Thr Val Asn Glu Asp Ser Glu Gly Arg AspLeu 215 220 225 cgg caa gtg acc tcc acg acc aag cta tgc agg gag aaa actgaa ctc 897 Arg Gln Val Thr Ser Thr Thr Lys Leu Cys Arg Glu Lys Thr GluLeu 230 235 240 act gta gac cag cag acc ctc ctg gat tat att atg gac tcatac agc 945 Thr Val Asp Gln Gln Thr Leu Leu Asp Tyr Ile Met Asp Ser TyrSer 245 250 255 aaa cag aga atg cca cag gag atc aca aat aaa atc tta aaagaa gaa 993 Lys Gln Arg Met Pro Gln Glu Ile Thr Asn Lys Ile Leu Lys GluGlu 260 265 270 ttt agt gca gaa gaa aat ttt ctc ata tta aca gaa atg gctacc agt 1041 Phe Ser Ala Glu Glu Asn Phe Leu Ile Leu Thr Glu Met Ala ThrSer 275 280 285 290 cac gta cag att ctc gta gaa ttc aca aaa aga ctt ccaggg ttt cag 1089 His Val Gln Ile Leu Val Glu Phe Thr Lys Arg Leu Pro GlyPhe Gln 295 300 305 aca ctg gac cac gaa gac cag att gct ttg ctc aaa gggtcc gca gtc 1137 Thr Leu Asp His Glu Asp Gln Ile Ala Leu Leu Lys Gly SerAla Val 310 315 320 gag gcc atg ttc ctt cgt tca gcg gag att ttc aat aagaaa ctt cct 1185 Glu Ala Met Phe Leu Arg Ser Ala Glu Ile Phe Asn Lys LysLeu Pro 325 330 335 gcc gga cac gca gac ctg ttg gaa gaa aga att cga aagagc ggc atc 1233 Ala Gly His Ala Asp Leu Leu Glu Glu Arg Ile Arg Lys SerGly Ile 340 345 350 tcc gat gag tac ata acc ccg atg ttt agt ttc tat aaaagt gtc ggg 1281 Ser Asp Glu Tyr Ile Thr Pro Met Phe Ser Phe Tyr Lys SerVal Gly 355 360 365 370 gag ctg aaa atg acc cag gaa gag tac gct ctg ctcaca gca att gtc 1329 Glu Leu Lys Met Thr Gln Glu Glu Tyr Ala Leu Leu ThrAla Ile Val 375 380 385 atc ctc tct cca gac aga caa tac ata aag gat agagag gca gtg gag 1377 Ile Leu Ser Pro Asp Arg Gln Tyr Ile Lys Asp Arg GluAla Val Glu 390 395 400 aag ctt cag gag cct ctg ctc gat gtc cta caa aaactc tgc aag atc 1425 Lys Leu Gln Glu Pro Leu Leu Asp Val Leu Gln Lys LeuCys Lys Ile 405 410 415 tac cag ccc gag aac cct cag cat ttc gcc tgc ctcctg ggt cgc ctg 1473 Tyr Gln Pro Glu Asn Pro Gln His Phe Ala Cys Leu LeuGly Arg Leu 420 425 430 aca gaa ctc cgg aca ttc aac cat cac cac gct gagatg ctg atg tct 1521 Thr Glu Leu Arg Thr Phe Asn His His His Ala Glu MetLeu Met Ser 435 440 445 450 tgg agg gtg aat gac cac aag ttc acc ccg ctcctc tgt gag atc tgg 1569 Trp Arg Val Asn Asp His Lys Phe Thr Pro Leu LeuCys Glu Ile Trp 455 460 465 gat gtg cag tga aggacacggg gagaggctagctccttgtcc tcctcagagc 1621 Asp Val Gln * agcaacctgg tattggacttcccttctttt catttgtacc aggtctcact caagaatctc 1681 aatgaatatt tatgtggcaattatacaatt cccacaactg taaatacagg ctccatagaa 1741 ttgcttcccc tacactgtattttacaaggc ttcgggaaac cccactgaca cgcccttttt 1801 gcctcattaa atcaattgttacttcaattt tgtcaactga gctagggacc gcctcgtttt 1861 atcctccatg cggcaacattatatatatat atattttatc aaatagctgt tttctcttcc 1921 tttttttttt ttttttttttcggagctggg gactgaaccc agggccttgc gcttgctagg 1981 caagcgctct accactgagctaaatcccca acccctatta aatagctgtt ttcaactgag 2041 acaataaact gaacgtaatgccaagagaa 2070 6 469 PRT Rattus norvegicus 6 Met Asn Leu Ile Gly Pro SerHis Leu Gln Ala Thr Asp Glu Phe Ala 1 5 10 15 Leu Ser Glu Asn Leu PheGly Val Leu Thr Glu His Ala Ala Gly Pro 20 25 30 Leu Gly Gln Asn Leu AspLeu Glu Ser Tyr Ser Pro Tyr Asn Asn Val 35 40 45 Gln Phe Pro Gln Val GlnPro Gln Ile Ser Ser Ser Ser Tyr Tyr Ser 50 55 60 Asn Leu Gly Phe Tyr ProGln Gln Pro Glu Asp Trp Tyr Ser Pro Gly 65 70 75 80 Leu Tyr Glu Leu ArgArg Met Pro Thr Glu Ser Val Tyr Gln Gly Glu 85 90 95 Thr Glu Val Ser GluMet Pro Val Thr Lys Lys Pro Arg Met Ala Ala 100 105 110 Ser Ser Ala GlyArg Ile Lys Gly Asp Glu Leu Cys Val Val Cys Gly 115 120 125 Asp Arg AlaSer Gly Tyr His Tyr Asn Ala Leu Thr Cys Glu Gly Cys 130 135 140 Lys GlyPhe Phe Arg Arg Ser Ile Thr Lys Asn Ala Val Tyr Lys Cys 145 150 155 160Lys Asn Gly Gly Asn Cys Val Met Asp Met Tyr Met Arg Arg Lys Cys 165 170175 Gln Asp Cys Arg Leu Arg Lys Cys Arg Glu Met Gly Met Leu Ala Glu 180185 190 Cys Leu Leu Thr Glu Ile Gln Cys Lys Ser Lys Arg Leu Arg Lys Asn195 200 205 Val Lys Gln His Ala Asp Gln Thr Val Asn Glu Asp Ser Glu GlyArg 210 215 220 Asp Leu Arg Gln Val Thr Ser Thr Thr Lys Leu Cys Arg GluLys Thr 225 230 235 240 Glu Leu Thr Val Asp Gln Gln Thr Leu Leu Asp TyrIle Met Asp Ser 245 250 255 Tyr Ser Lys Gln Arg Met Pro Gln Glu Ile ThrAsn Lys Ile Leu Lys 260 265 270 Glu Glu Phe Ser Ala Glu Glu Asn Phe LeuIle Leu Thr Glu Met Ala 275 280 285 Thr Ser His Val Gln Ile Leu Val GluPhe Thr Lys Arg Leu Pro Gly 290 295 300 Phe Gln Thr Leu Asp His Glu AspGln Ile Ala Leu Leu Lys Gly Ser 305 310 315 320 Ala Val Glu Ala Met PheLeu Arg Ser Ala Glu Ile Phe Asn Lys Lys 325 330 335 Leu Pro Ala Gly HisAla Asp Leu Leu Glu Glu Arg Ile Arg Lys Ser 340 345 350 Gly Ile Ser AspGlu Tyr Ile Thr Pro Met Phe Ser Phe Tyr Lys Ser 355 360 365 Val Gly GluLeu Lys Met Thr Gln Glu Glu Tyr Ala Leu Leu Thr Ala 370 375 380 Ile ValIle Leu Ser Pro Asp Arg Gln Tyr Ile Lys Asp Arg Glu Ala 385 390 395 400Val Glu Lys Leu Gln Glu Pro Leu Leu Asp Val Leu Gln Lys Leu Cys 405 410415 Lys Ile Tyr Gln Pro Glu Asn Pro Gln His Phe Ala Cys Leu Leu Gly 420425 430 Arg Leu Thr Glu Leu Arg Thr Phe Asn His His His Ala Glu Met Leu435 440 445 Met Ser Trp Arg Val Asn Asp His Lys Phe Thr Pro Leu Leu CysGlu 450 455 460 Ile Trp Asp Val Gln 465 7 2218 DNA Homo Sapien CDS(354)...(1772) GeneBank NM_005123 2002-11-05 7 acgagactct ctcctcctcctcacctcatt gtctccccga cttatcctaa tgcgaaattg 60 gattctgagc atttgtagcaaaatcgctgg gatctggaga ggaagactca gtccagaatc 120 ctcccagggc cttgaaagtccatctctgac ccaaaacaat ccaaggaggt agaagacatc 180 gtagaaggag tgaaagaagaaaagaagact tagaaacata gctcaaagtg aacactgctt 240 ctcttagttt cctggatttcttctggacat ttcctcaaga tgaaacttca gacactttgg 300 agtttttttt gaagaccaccataaagaaag tgcatttcaa ttgaaaaatt tgg atg 356 Met 1 gga tca aaa atg aatctc att gaa cat tcc cat tta cct acc aca gat 404 Gly Ser Lys Met Asn LeuIle Glu His Ser His Leu Pro Thr Thr Asp 5 10 15 gaa ttt tct ttt tct gaaaat tta ttt ggt gtt tta aca gaa caa gtg 452 Glu Phe Ser Phe Ser Glu AsnLeu Phe Gly Val Leu Thr Glu Gln Val 20 25 30 gca ggt cct ctg gga cag aacctg gaa gtg gaa cca tac tcg caa tac 500 Ala Gly Pro Leu Gly Gln Asn LeuGlu Val Glu Pro Tyr Ser Gln Tyr 35 40 45 agc aat gtt cag ttt ccc caa gttcaa cca cag att tcc tcg tca tcc 548 Ser Asn Val Gln Phe Pro Gln Val GlnPro Gln Ile Ser Ser Ser Ser 50 55 60 65 tat tat tcc aac ctg ggt ttc tacccc cag cag cct gaa gag tgg tac 596 Tyr Tyr Ser Asn Leu Gly Phe Tyr ProGln Gln Pro Glu Glu Trp Tyr 70 75 80 tct cct gga ata tat gaa ctc agg cgtatg cca gct gag act ctc tac 644 Ser Pro Gly Ile Tyr Glu Leu Arg Arg MetPro Ala Glu Thr Leu Tyr 85 90 95 cag gga gaa act gag gta gca gag atg cctgta aca aag aag ccc cgc 692 Gln Gly Glu Thr Glu Val Ala Glu Met Pro ValThr Lys Lys Pro Arg 100 105 110 atg ggc gcg tca gca ggg agg atc aaa ggggat gag ctg tgt gtt gtt 740 Met Gly Ala Ser Ala Gly Arg Ile Lys Gly AspGlu Leu Cys Val Val 115 120 125 tgt gga gac aga gcc tct gga tac cac tataat gca ctg acc tgt gag 788 Cys Gly Asp Arg Ala Ser Gly Tyr His Tyr AsnAla Leu Thr Cys Glu 130 135 140 145 ggg tgt aaa ggt ttc ttc agg aga agcatt acc aaa aac gct gtg tac 836 Gly Cys Lys Gly Phe Phe Arg Arg Ser IleThr Lys Asn Ala Val Tyr 150 155 160 aag tgt aaa aac ggg ggc aac tgt gtgatg gat atg tac atg cga aga 884 Lys Cys Lys Asn Gly Gly Asn Cys Val MetAsp Met Tyr Met Arg Arg 165 170 175 aag tgt caa gag tgt cga cta agg aaatgc aaa gag atg gga atg ttg 932 Lys Cys Gln Glu Cys Arg Leu Arg Lys CysLys Glu Met Gly Met Leu 180 185 190 gct gaa tgc ttg tta act gaa att cagtgt aaa tct aag cga ctg aga 980 Ala Glu Cys Leu Leu Thr Glu Ile Gln CysLys Ser Lys Arg Leu Arg 195 200 205 aaa aat gtg aag cag cat gca gat cagacc gtg aat gaa gac agt gaa 1028 Lys Asn Val Lys Gln His Ala Asp Gln ThrVal Asn Glu Asp Ser Glu 210 215 220 225 ggt cgt gac ttg cga caa gtg acctcg aca aca aag tca tgc agg gag 1076 Gly Arg Asp Leu Arg Gln Val Thr SerThr Thr Lys Ser Cys Arg Glu 230 235 240 aaa act gaa ctc acc cca gat caacag act ctt cta cat ttt att atg 1124 Lys Thr Glu Leu Thr Pro Asp Gln GlnThr Leu Leu His Phe Ile Met 245 250 255 gat tca tat aac aaa cag agg atgcct cag gaa ata aca aat aaa att 1172 Asp Ser Tyr Asn Lys Gln Arg Met ProGln Glu Ile Thr Asn Lys Ile 260 265 270 tta aaa gaa gaa ttc agt gca gaagaa aat ttt ctc att ttg acg gaa 1220 Leu Lys Glu Glu Phe Ser Ala Glu GluAsn Phe Leu Ile Leu Thr Glu 275 280 285 atg gca acc aat cat gta cag gttctt gta gaa ttc aca aaa aag cta 1268 Met Ala Thr Asn His Val Gln Val LeuVal Glu Phe Thr Lys Lys Leu 290 295 300 305 cca gga ttt cag act ttg gaccat gaa gac cag att gct ttg ctg aaa 1316 Pro Gly Phe Gln Thr Leu Asp HisGlu Asp Gln Ile Ala Leu Leu Lys 310 315 320 ggg tct gcg gtt gaa gct atgttc ctt cgt tca gct gag att ttc aat 1364 Gly Ser Ala Val Glu Ala Met PheLeu Arg Ser Ala Glu Ile Phe Asn 325 330 335 aag aaa ctt ccg tct ggg cattct gac cta ttg gaa gaa aga att cga 1412 Lys Lys Leu Pro Ser Gly His SerAsp Leu Leu Glu Glu Arg Ile Arg 340 345 350 aat agt ggt atc tct gat gaatat ata aca cct atg ttt agt ttt tat 1460 Asn Ser Gly Ile Ser Asp Glu TyrIle Thr Pro Met Phe Ser Phe Tyr 355 360 365 aaa agt att ggg gaa ctg aaaatg act caa gag gag tat gct ctg ctt 1508 Lys Ser Ile Gly Glu Leu Lys MetThr Gln Glu Glu Tyr Ala Leu Leu 370 375 380 385 aca gca att gtt atc ctgtct cca gat aga caa tac ata aag gat aga 1556 Thr Ala Ile Val Ile Leu SerPro Asp Arg Gln Tyr Ile Lys Asp Arg 390 395 400 gag gca gta gag aag cttcag gag cca ctt ctt gat gtg cta caa aag 1604 Glu Ala Val Glu Lys Leu GlnGlu Pro Leu Leu Asp Val Leu Gln Lys 405 410 415 ttg tgt aag att cac cagcct gaa aat cct caa cac ttt gcc tgt ctc 1652 Leu Cys Lys Ile His Gln ProGlu Asn Pro Gln His Phe Ala Cys Leu 420 425 430 ctg ggt cgc ctg act gaatta cgg aca ttc aat cat cac cac gct gag 1700 Leu Gly Arg Leu Thr Glu LeuArg Thr Phe Asn His His His Ala Glu 435 440 445 atg ctg atg tca tgg agagta aac gac cac aag ttt acc cca ctt ctc 1748 Met Leu Met Ser Trp Arg ValAsn Asp His Lys Phe Thr Pro Leu Leu 450 455 460 465 tgt gaa atc tgg gacgtg cag tga tggggattac aggggagggg tctagctcct 1802 Cys Glu Ile Trp AspVal Gln * 470 ttttctctct catattaatc tgatgtataa ctttccttta tttcacttgtacccagtttc 1862 actcaagaaa tcttgatgaa tatttatgtt gtaattacat gtgtaacttccacaactgta 1922 aatattgggc tagatagaac aactttctct acattgtgtt ttaaaaggctccagggaatc 1982 ctgcattcta attggcaagc cctgtttgcc taattaaatt gattgttacttcaattctat 2042 ctgttgaact agggaaaatc tcattttgct catcttacca tattgcatatattttattaa 2102 agagttgtat tcaatcttgg caataaagca aacataatgg caacagaaaaaaaaaaaaaa 2162 aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaaaaaaaa 2218 8 472 PRT Homo Sapien 8 Met Gly Ser Lys Met Asn Leu Ile GluHis Ser His Leu Pro Thr Thr 1 5 10 15 Asp Glu Phe Ser Phe Ser Glu AsnLeu Phe Gly Val Leu Thr Glu Gln 20 25 30 Val Ala Gly Pro Leu Gly Gln AsnLeu Glu Val Glu Pro Tyr Ser Gln 35 40 45 Tyr Ser Asn Val Gln Phe Pro GlnVal Gln Pro Gln Ile Ser Ser Ser 50 55 60 Ser Tyr Tyr Ser Asn Leu Gly PheTyr Pro Gln Gln Pro Glu Glu Trp 65 70 75 80 Tyr Ser Pro Gly Ile Tyr GluLeu Arg Arg Met Pro Ala Glu Thr Leu 85 90 95 Tyr Gln Gly Glu Thr Glu ValAla Glu Met Pro Val Thr Lys Lys Pro 100 105 110 Arg Met Gly Ala Ser AlaGly Arg Ile Lys Gly Asp Glu Leu Cys Val 115 120 125 Val Cys Gly Asp ArgAla Ser Gly Tyr His Tyr Asn Ala Leu Thr Cys 130 135 140 Glu Gly Cys LysGly Phe Phe Arg Arg Ser Ile Thr Lys Asn Ala Val 145 150 155 160 Tyr LysCys Lys Asn Gly Gly Asn Cys Val Met Asp Met Tyr Met Arg 165 170 175 ArgLys Cys Gln Glu Cys Arg Leu Arg Lys Cys Lys Glu Met Gly Met 180 185 190Leu Ala Glu Cys Leu Leu Thr Glu Ile Gln Cys Lys Ser Lys Arg Leu 195 200205 Arg Lys Asn Val Lys Gln His Ala Asp Gln Thr Val Asn Glu Asp Ser 210215 220 Glu Gly Arg Asp Leu Arg Gln Val Thr Ser Thr Thr Lys Ser Cys Arg225 230 235 240 Glu Lys Thr Glu Leu Thr Pro Asp Gln Gln Thr Leu Leu HisPhe Ile 245 250 255 Met Asp Ser Tyr Asn Lys Gln Arg Met Pro Gln Glu IleThr Asn Lys 260 265 270 Ile Leu Lys Glu Glu Phe Ser Ala Glu Glu Asn PheLeu Ile Leu Thr 275 280 285 Glu Met Ala Thr Asn His Val Gln Val Leu ValGlu Phe Thr Lys Lys 290 295 300 Leu Pro Gly Phe Gln Thr Leu Asp His GluAsp Gln Ile Ala Leu Leu 305 310 315 320 Lys Gly Ser Ala Val Glu Ala MetPhe Leu Arg Ser Ala Glu Ile Phe 325 330 335 Asn Lys Lys Leu Pro Ser GlyHis Ser Asp Leu Leu Glu Glu Arg Ile 340 345 350 Arg Asn Ser Gly Ile SerAsp Glu Tyr Ile Thr Pro Met Phe Ser Phe 355 360 365 Tyr Lys Ser Ile GlyGlu Leu Lys Met Thr Gln Glu Glu Tyr Ala Leu 370 375 380 Leu Thr Ala IleVal Ile Leu Ser Pro Asp Arg Gln Tyr Ile Lys Asp 385 390 395 400 Arg GluAla Val Glu Lys Leu Gln Glu Pro Leu Leu Asp Val Leu Gln 405 410 415 LysLeu Cys Lys Ile His Gln Pro Glu Asn Pro Gln His Phe Ala Cys 420 425 430Leu Leu Gly Arg Leu Thr Glu Leu Arg Thr Phe Asn His His His Ala 435 440445 Glu Met Leu Met Ser Trp Arg Val Asn Asp His Lys Phe Thr Pro Leu 450455 460 Leu Cys Glu Ile Trp Asp Val Gln 465 470 9 5449 DNA Homo SapienCDS (69)...(1457) GeneBank NM_002957 2002-06-21 9 gcgccggggg ccgccgcgcccgccgcccgc tgcctgcgcc gccggccggg catgagttag 60 tcgcagac atg gac acc aaacat ttc ctg ccg ctc gat ttc tcc acc cag 110 Met Asp Thr Lys His Phe LeuPro Leu Asp Phe Ser Thr Gln 1 5 10 gtg aac tcc tcc ctc acc tcc ccg acgggg cga ggc tcc atg gct gcc 158 Val Asn Ser Ser Leu Thr Ser Pro Thr GlyArg Gly Ser Met Ala Ala 15 20 25 30 ccc tcg ctg cac ccg tcc ctg ggg cctggc atc ggc tcc ccg gga cag 206 Pro Ser Leu His Pro Ser Leu Gly Pro GlyIle Gly Ser Pro Gly Gln 35 40 45 ctg cat tct ccc atc agc acc ctg agc tccccc atc aac ggc atg ggc 254 Leu His Ser Pro Ile Ser Thr Leu Ser Ser ProIle Asn Gly Met Gly 50 55 60 ccg cct ttc tcg gtc atc agc tcc ccc atg ggcccc cac tcc atg tcg 302 Pro Pro Phe Ser Val Ile Ser Ser Pro Met Gly ProHis Ser Met Ser 65 70 75 gtg ccc acc aca ccc acc ctg ggc ttc agc act ggcagc ccc cag ctc 350 Val Pro Thr Thr Pro Thr Leu Gly Phe Ser Thr Gly SerPro Gln Leu 80 85 90 agc tca cct atg aac ccc gtc agc agc agc gag gac atcaag ccc ccc 398 Ser Ser Pro Met Asn Pro Val Ser Ser Ser Glu Asp Ile LysPro Pro 95 100 105 110 ctg ggc ctc aat ggc gtc ctc aag gtc ccc gcc cacccc tca gga aac 446 Leu Gly Leu Asn Gly Val Leu Lys Val Pro Ala His ProSer Gly Asn 115 120 125 atg gct tcc ttc acc aag cac atc tgc gcc atc tgcggg gac cgc tcc 494 Met Ala Ser Phe Thr Lys His Ile Cys Ala Ile Cys GlyAsp Arg Ser 130 135 140 tca ggc aag cac tat gga gtg tac agc tgc gag gggtgc aag ggc ttc 542 Ser Gly Lys His Tyr Gly Val Tyr Ser Cys Glu Gly CysLys Gly Phe 145 150 155 ttc aag cgg acg gtg cgc aag gac ctg acc tac acctgc cgc gac aac 590 Phe Lys Arg Thr Val Arg Lys Asp Leu Thr Tyr Thr CysArg Asp Asn 160 165 170 aag gac tgc ctg att gac aag cgg cag cgg aac cggtgc cag tac tgc 638 Lys Asp Cys Leu Ile Asp Lys Arg Gln Arg Asn Arg CysGln Tyr Cys 175 180 185 190 cgc tac cag aag tgc ctg gcc atg ggc atg aagcgg gaa gcc gtg cag 686 Arg Tyr Gln Lys Cys Leu Ala Met Gly Met Lys ArgGlu Ala Val Gln 195 200 205 gag gag cgg cag cgt ggc aag gac cgg aac gagaat gag gtg gag tcg 734 Glu Glu Arg Gln Arg Gly Lys Asp Arg Asn Glu AsnGlu Val Glu Ser 210 215 220 acc agc agc gcc aac gag gac atg ccg gtg gagagg atc ctg gag gct 782 Thr Ser Ser Ala Asn Glu Asp Met Pro Val Glu ArgIle Leu Glu Ala 225 230 235 gag ctg gcc gtg gag ccc aag acc gag acc tacgtg gag gca aac atg 830 Glu Leu Ala Val Glu Pro Lys Thr Glu Thr Tyr ValGlu Ala Asn Met 240 245 250 ggg ctg aac ccc agc tcg ccg aac gac cct gtcacc aac att tgc caa 878 Gly Leu Asn Pro Ser Ser Pro Asn Asp Pro Val ThrAsn Ile Cys Gln 255 260 265 270 gca gcc gac aaa cag ctt ttc acc ctg gtggag tgg gcc aag cgg atc 926 Ala Ala Asp Lys Gln Leu Phe Thr Leu Val GluTrp Ala Lys Arg Ile 275 280 285 cca cac ttc tca gag ctg ccc ctg gac gaccag gtc atc ctg ctg cgg 974 Pro His Phe Ser Glu Leu Pro Leu Asp Asp GlnVal Ile Leu Leu Arg 290 295 300 gca ggc tgg aat gag ctg ctc atc gcc tccttc tcc cac cgc tcc atc 1022 Ala Gly Trp Asn Glu Leu Leu Ile Ala Ser PheSer His Arg Ser Ile 305 310 315 gcc gtg aag gac ggg atc ctc ctg gcc accggg ctg cac gtc cac cgg 1070 Ala Val Lys Asp Gly Ile Leu Leu Ala Thr GlyLeu His Val His Arg 320 325 330 aac agc gcc cac agc gca ggg gtg ggc gccatc ttt gac agg gtg ctg 1118 Asn Ser Ala His Ser Ala Gly Val Gly Ala IlePhe Asp Arg Val Leu 335 340 345 350 acg gag ctt gtg tcc aag atg cgg gacatg cag atg gac aag acg gag 1166 Thr Glu Leu Val Ser Lys Met Arg Asp MetGln Met Asp Lys Thr Glu 355 360 365 ctg ggc tgc ctg cgc gcc atc gtc ctcttt aac cct gac tcc aag ggg 1214 Leu Gly Cys Leu Arg Ala Ile Val Leu PheAsn Pro Asp Ser Lys Gly 370 375 380 ctc tcg aac ccg gcc gag gtg gag gcgctg agg gag aag gtc tat gcg 1262 Leu Ser Asn Pro Ala Glu Val Glu Ala LeuArg Glu Lys Val Tyr Ala 385 390 395 tcc ttg gag gcc tac tgc aag cac aagtac cca gag cag ccg gga agg 1310 Ser Leu Glu Ala Tyr Cys Lys His Lys TyrPro Glu Gln Pro Gly Arg 400 405 410 ttc gct aag ctc ttg ctc cgc ctg ccggct ctg cgc tcc atc ggg ctc 1358 Phe Ala Lys Leu Leu Leu Arg Leu Pro AlaLeu Arg Ser Ile Gly Leu 415 420 425 430 aaa tgc ctg gaa cat ctc ttc ttcttc aag ctc atc ggg gac aca ccc 1406 Lys Cys Leu Glu His Leu Phe Phe PheLys Leu Ile Gly Asp Thr Pro 435 440 445 att gac acc ttc ctt atg gag atgctg gag gcg ccg cac caa atg act 1454 Ile Asp Thr Phe Leu Met Glu Met LeuGlu Ala Pro His Gln Met Thr 450 455 460 tag gcctgcgggc ccatcctttgtgcccacccg ttctggccac cctgcctgga 1507 * cgccagctgt tcttctcagc ctgagccctgtccctgccct tctctgcctg gcctgtttgg 1567 actttggggc acagcctgtc actgctctgcctaagagatg tgttgtcacc ctccttattt 1627 ctgttactac ttgtctgtgg cccagggcagtggctttcct gaggcagcag ccttcgtggc 1687 aagaactagc gtgagcccag ccaggcgcctccccaccggg ctctcaggac accctgccac 1747 accccacggg gcttgggcga ctacagggtcttcgggcccc agccctggag ctgcaggagt 1807 tgggaacggg gcttttgttt ccgttgctgtttatcgatgc tggttttcag aattcctgtg 1867 tggccctcct gtctggagtg acatcttcatctgctctgaa tactggtgcc cagccagccc 1927 gtgacagctt ccccctaatc aggaggggacagctgggggc gcaagctggt gtgtcatcag 1987 caaagacctc agccgcctcg gggatgagaggggactcgtg gggcaagcaa gctgccctgt 2047 gctctgagtg agggggaagg tagcccctttttccaaagat aactcacagt tttgccctcg 2107 agccaatgag aacatgagct gccctctgtgcaaggtttcg gggccacctc caggctgcag 2167 gggcgggtca ctcacccccc tgttttctctctgccttggt gttctggttt cagactcccg 2227 actccccgtt cagaccagag tgccccggcccctccccagc ctgagtcttc tccttgctct 2287 gcggggtggg ctgaggcttg tccttgtttcctgcagggct ggccctggct cgggcagggt 2347 ggggcatcac cacctcactg gccttgctggaggcacaggg ctctgcggac ctgcagccat 2407 ctgtgaggcc cgcggggatg ggaggggaggagggtggcct gttggtttcc ctcagagggg 2467 gcaggtggcc tggagagaga ggggctcaggaactgggagc ctcgtgggtg gggcagatgc 2527 tccgcggcct ggagtggctc tgccggggcattggtgggac ccctgctcag gccttctctc 2587 tggctgccag ttgtgtctaa aagactcttggaatctgaga acccggagtc gcagcgccct 2647 cgggcctggg ccacacgcag gccctggtgggaccacccag cctggtattg tccacggaca 2707 gcgttgttca cccagagcct tacttgggagcctcactgaa cgcctgctct ggttgaaggt 2767 ggggtggggg cggggcttgg ggcctccctggctcagccca gtgcggcctg gcgctcctcc 2827 cgcaggctct gcccccgggc tccggtggtgcggggccctc tcaggttgaa ctcgcctctt 2887 ttgcactgga aggccctccc tttggcctgagtacttttcc cgttcacgcc tcagtcccgt 2947 ggacccagcc tttgtcagtg gcaggtgcctgaacagaggg tggatggggg ggataccgga 3007 gggggtcttg tcttcccagc cgcagtctaggaatgatgcg ggggggtgga cgccttctcc 3067 atagtctttc cccacctgga gcaggggcttcctcagtggt gaggggagct gcctacaggt 3127 tggaccggga ggcagtggct tggagaggcagctttccagc cttggtgggg aagaaagtgt 3187 ccattctttg ccttcctgga gctcccagccagagctgagc ttaggcaccc gagtggagcc 3247 tgcagctgag tctgtgcccg agacaggctgtcagagattc cagaagcctc tcctccccgc 3307 cgccctccac ccctgccttt cagcgttgtggatccctaga ggtggccccc tgcccgatcc 3367 accgtcctga ggcagagtgt tgagcctcatacctgtacca ggtccccggc cagctgggcc 3427 cctcccaggc actgccagga agccccagctgcccctggcg ggtgtggtgg aaatggcagg 3487 agggtgcagg tactcttggg gccccagcggtgggagtgca aaagacccaa cgccaacacc 3547 tggtgccttt tgcagccagc gcccacccatccgtgcccgg acccttggga atgcccgcgg 3607 ctccagagga aaaagcccag ggacggggcctccgttgcgg ggggtcggct gcttcttggg 3667 aactttgtcg tttccggcgc tggctggctggctggctgta aagcactgaa gccccccggc 3727 cgccaacccc tgaaagcaga acctggcctccctggccaca gcagccttac ccaccgctct 3787 acgtgtcccg ggcacttccc gcagccttcccgtccctttc tcatcggcct tgtagttgta 3847 cagtgctgtt ggtttgaaaa ggtgatgtgtggggagtgcg gctcatcact gagtagagag 3907 gtagaatttc tatttaacca gacctgtagtagtattacca atccagttca attaaggtga 3967 ttttttgtaa ttattattat tttggtgggacaatctttaa ttttctaaag atagcactaa 4027 catcagctca ttagccacct gtgcctgtccccgccttggc ccggctggat gaagcggctt 4087 ccccgcaggg cccccacttc ccagtggctgcttcctgggg acccagggca ccccggcacc 4147 ttcaggcacg ctcctcagct ggtcacctcccggctttgcc gttcagatgg ggctcctgag 4207 gctcaggagt gaagatgcca cagagccgggctcccctagg ctgcgtcggg catgcttgga 4267 agctggcctg ccaggacctt ccaccctggggcctgtgtca gccgccggcc ctccgcaccc 4327 tggaagcaca cggcctctgg gaaggacagccctgaccttc ggttttccga gcacggtgtt 4387 tcccaagaat tctgggctgg cggcctggtggcagtgctgg agatgacccc gagcccctcc 4447 ccgtggggca cccaggaggg ccctgccggaatgtgcagcc tgtgggtagt cggctggtgt 4507 ccctgtcgtg gagctggggt gcgtgatctggtgctcgtcc acgcaggtgt gtggtgtaaa 4567 catgtatgtg ctgtacagag agacgcgtgtggagagagcc gcacaccagc gccacccagg 4627 aaaggcggag cggttaccag tgttttgtgtttatttttaa tcaagacgtt tcccctgttt 4687 tcctataaat ttgcttcgtg taagcaagtacataaggacc ctcctttggt gaaatccggg 4747 ttcgaatgaa tatctcaagg caggagatgcatctatttta agatgctttg gagcagacag 4807 ctttagccgt tcccaatcct tagcaatgccttagctggga cgcatagcta atactttaga 4867 gaggatgaca gatccataaa gagagtaaagataagagaaa atgtctaaag catctggaaa 4927 ggtaaaaaaa aaaaatctat ttttgtacaaatgtaatttt atccctcatg tatacttgga 4987 tatggcgggg ggagggctgg gactgtttcgtttctgcttc tagagattga ggtgaaagct 5047 tcgtccgaga aacgccagga cagacgatggcagaggagag ggctcctgtg acggcggcga 5107 ggcttgggag gaaaccgccg caatgggggtgtcttccctc ggggcaggag ggtgggcctg 5167 aggctttcaa gggttttctt ccctttcgagtaatttttaa agccttgctc tgttgtgtcc 5227 tgttgccggc tctggccttc ctgtgactgactgtgaagtg gcttctccgt acgattgtct 5287 ctgaaacatc gtggcctcag gtgccagggtttgatggaca gtagcattag aattgtggaa 5347 aaggaacacg caaagggaga agtgtgagaggagaaacaaa atatgagcgt ttaaaataca 5407 tcgccattca gttcgttaaa aaaaaaaaaaaaaaaaaaaa aa 5449 10 462 PRT Homo Sapien 10 Met Asp Thr Lys His Phe LeuPro Leu Asp Phe Ser Thr Gln Val Asn 1 5 10 15 Ser Ser Leu Thr Ser ProThr Gly Arg Gly Ser Met Ala Ala Pro Ser 20 25 30 Leu His Pro Ser Leu GlyPro Gly Ile Gly Ser Pro Gly Gln Leu His 35 40 45 Ser Pro Ile Ser Thr LeuSer Ser Pro Ile Asn Gly Met Gly Pro Pro 50 55 60 Phe Ser Val Ile Ser SerPro Met Gly Pro His Ser Met Ser Val Pro 65 70 75 80 Thr Thr Pro Thr LeuGly Phe Ser Thr Gly Ser Pro Gln Leu Ser Ser 85 90 95 Pro Met Asn Pro ValSer Ser Ser Glu Asp Ile Lys Pro Pro Leu Gly 100 105 110 Leu Asn Gly ValLeu Lys Val Pro Ala His Pro Ser Gly Asn Met Ala 115 120 125 Ser Phe ThrLys His Ile Cys Ala Ile Cys Gly Asp Arg Ser Ser Gly 130 135 140 Lys HisTyr Gly Val Tyr Ser Cys Glu Gly Cys Lys Gly Phe Phe Lys 145 150 155 160Arg Thr Val Arg Lys Asp Leu Thr Tyr Thr Cys Arg Asp Asn Lys Asp 165 170175 Cys Leu Ile Asp Lys Arg Gln Arg Asn Arg Cys Gln Tyr Cys Arg Tyr 180185 190 Gln Lys Cys Leu Ala Met Gly Met Lys Arg Glu Ala Val Gln Glu Glu195 200 205 Arg Gln Arg Gly Lys Asp Arg Asn Glu Asn Glu Val Glu Ser ThrSer 210 215 220 Ser Ala Asn Glu Asp Met Pro Val Glu Arg Ile Leu Glu AlaGlu Leu 225 230 235 240 Ala Val Glu Pro Lys Thr Glu Thr Tyr Val Glu AlaAsn Met Gly Leu 245 250 255 Asn Pro Ser Ser Pro Asn Asp Pro Val Thr AsnIle Cys Gln Ala Ala 260 265 270 Asp Lys Gln Leu Phe Thr Leu Val Glu TrpAla Lys Arg Ile Pro His 275 280 285 Phe Ser Glu Leu Pro Leu Asp Asp GlnVal Ile Leu Leu Arg Ala Gly 290 295 300 Trp Asn Glu Leu Leu Ile Ala SerPhe Ser His Arg Ser Ile Ala Val 305 310 315 320 Lys Asp Gly Ile Leu LeuAla Thr Gly Leu His Val His Arg Asn Ser 325 330 335 Ala His Ser Ala GlyVal Gly Ala Ile Phe Asp Arg Val Leu Thr Glu 340 345 350 Leu Val Ser LysMet Arg Asp Met Gln Met Asp Lys Thr Glu Leu Gly 355 360 365 Cys Leu ArgAla Ile Val Leu Phe Asn Pro Asp Ser Lys Gly Leu Ser 370 375 380 Asn ProAla Glu Val Glu Ala Leu Arg Glu Lys Val Tyr Ala Ser Leu 385 390 395 400Glu Ala Tyr Cys Lys His Lys Tyr Pro Glu Gln Pro Gly Arg Phe Ala 405 410415 Lys Leu Leu Leu Arg Leu Pro Ala Leu Arg Ser Ile Gly Leu Lys Cys 420425 430 Leu Glu His Leu Phe Phe Phe Lys Leu Ile Gly Asp Thr Pro Ile Asp435 440 445 Thr Phe Leu Met Glu Met Leu Glu Ala Pro His Gln Met Thr 450455 460 11 2081 DNA Mus musculus CDS (167)...(1573) GeneBank X576381991-03-19 11 gtcacagcct aggctttgct ggggacctga gaaacgctgc cgccaagttgaagttcaagg 60 ccctgccttc cctgtgaact gacgtttgtg gctggtcaag ttcgggaacaagacgttgtc 120 atcacagctt agcgctctgt ggcctgcctg gccacatcca tccaac atggtg gac 175 Met Val Asp 1 aca gag agc ccc atc tgt cct ctc tcc cca ctggag gca gat gac ctg 223 Thr Glu Ser Pro Ile Cys Pro Leu Ser Pro Leu GluAla Asp Asp Leu 5 10 15 gaa agt ccc tta tct gaa gaa ttc tta caa gaa atggga aac att caa 271 Glu Ser Pro Leu Ser Glu Glu Phe Leu Gln Glu Met GlyAsn Ile Gln 20 25 30 35 gag att tct cag tcc atc ggt gag gag agc tct ggaagc ttt ggt ttt 319 Glu Ile Ser Gln Ser Ile Gly Glu Glu Ser Ser Gly SerPhe Gly Phe 40 45 50 gca gac tac cag tac tta gga agc tgt ccg ggc tcc gagggc tct gtc 367 Ala Asp Tyr Gln Tyr Leu Gly Ser Cys Pro Gly Ser Glu GlySer Val 55 60 65 atc aca gac acc ctc tct cca cgt tcc agc cct tcc tca gtcagc tgc 415 Ile Thr Asp Thr Leu Ser Pro Arg Ser Ser Pro Ser Ser Val SerCys 70 75 80 ccc gtg atc ccc gcc agc acg gac gag tcc ccc ggc agt gcc ctgaac 463 Pro Val Ile Pro Ala Ser Thr Asp Glu Ser Pro Gly Ser Ala Leu Asn85 90 95 atc gag tgt cga ata tgt ggg gac aag gcc tca ggg tac cac tac gga511 Ile Glu Cys Arg Ile Cys Gly Asp Lys Ala Ser Gly Tyr His Tyr Gly 100105 110 115 gtt cac gca tgt gaa ggc tgt aag ggc ttc ttt cgg cga act attcgg 559 Val His Ala Cys Glu Gly Cys Lys Gly Phe Phe Arg Arg Thr Ile Arg120 125 130 ctg aag ctg gtg tac gac aag tgt gat cgg agc tgc aag att cagaag 607 Leu Lys Leu Val Tyr Asp Lys Cys Asp Arg Ser Cys Lys Ile Gln Lys135 140 145 aag aac cgg aac aaa tgc cag tac tgc cgt ttt cac aag tgc ctgtct 655 Lys Asn Arg Asn Lys Cys Gln Tyr Cys Arg Phe His Lys Cys Leu Ser150 155 160 gtc ggg atg tca cac aat gca att cgc ttt gga aga atg cca agatct 703 Val Gly Met Ser His Asn Ala Ile Arg Phe Gly Arg Met Pro Arg Ser165 170 175 gaa aaa gca aaa ctg aaa gca gaa att ctt acc tgt gaa cac gacctg 751 Glu Lys Ala Lys Leu Lys Ala Glu Ile Leu Thr Cys Glu His Asp Leu180 185 190 195 aaa gat tcg gaa act gca gac ctc aaa tct ctg ggc aag agaatc cac 799 Lys Asp Ser Glu Thr Ala Asp Leu Lys Ser Leu Gly Lys Arg IleHis 200 205 210 gaa gcc tac ctg aag aac ttc aac atg aac aag gtc aag gcccgg gtc 847 Glu Ala Tyr Leu Lys Asn Phe Asn Met Asn Lys Val Lys Ala ArgVal 215 220 225 ata ctc gcg gga aag acc agc aac aac ccg cct ttt gtc atacat gac 895 Ile Leu Ala Gly Lys Thr Ser Asn Asn Pro Pro Phe Val Ile HisAsp 230 235 240 atg gag acc ttg tgt atg gcc gag aag acg ctt gtg gcc aagatg gtg 943 Met Glu Thr Leu Cys Met Ala Glu Lys Thr Leu Val Ala Lys MetVal 245 250 255 gcc aac ggc gtc gaa gac aaa gag gca gag gtc cga ttc ttccac tgc 991 Ala Asn Gly Val Glu Asp Lys Glu Ala Glu Val Arg Phe Phe HisCys 260 265 270 275 tgc cag tgc atg tcc gtg gag acc gtc acg gag ctc acagaa ttt gcc 1039 Cys Gln Cys Met Ser Val Glu Thr Val Thr Glu Leu Thr GluPhe Ala 280 285 290 aag gct atc cca ggc ttt gca aac ttg gac ttg aac gaccaa gtc acc 1087 Lys Ala Ile Pro Gly Phe Ala Asn Leu Asp Leu Asn Asp GlnVal Thr 295 300 305 ttg cta aag tac ggt gtg tat gaa gcc atc ttc acg atgctg tcc tcc 1135 Leu Leu Lys Tyr Gly Val Tyr Glu Ala Ile Phe Thr Met LeuSer Ser 310 315 320 ttg atg aac aaa gac ggg atg ctg atc gcg tac ggc aatggc ttt atc 1183 Leu Met Asn Lys Asp Gly Met Leu Ile Ala Tyr Gly Asn GlyPhe Ile 325 330 335 aca cgc gag ttc ctt aag aac ctg agg aag ccg ttc tgtgac atc atg 1231 Thr Arg Glu Phe Leu Lys Asn Leu Arg Lys Pro Phe Cys AspIle Met 340 345 350 355 gaa ccc aag ttt gac ttc gct atg aag ttc aat gcctta gaa ctg gat 1279 Glu Pro Lys Phe Asp Phe Ala Met Lys Phe Asn Ala LeuGlu Leu Asp 360 365 370 gac agt gac att tcc ctg ttt gtg gct gct ata atttgc tgt gga gat 1327 Asp Ser Asp Ile Ser Leu Phe Val Ala Ala Ile Ile CysCys Gly Asp 375 380 385 cgg cct ggc ctt cta aac ata ggc tac att gag aagttg cag gag ggg 1375 Arg Pro Gly Leu Leu Asn Ile Gly Tyr Ile Glu Lys LeuGln Glu Gly 390 395 400 att gtg cac gtg ctt aag ctc cac ctg cag agc aaccat cca gat gac 1423 Ile Val His Val Leu Lys Leu His Leu Gln Ser Asn HisPro Asp Asp 405 410 415 acc ttc ctc ttc cca aag ctc ctt caa aaa atg gtggac ctt cgg cag 1471 Thr Phe Leu Phe Pro Lys Leu Leu Gln Lys Met Val AspLeu Arg Gln 420 425 430 435 ctg gtc acg gag cat gcg cag ctc gta cag gtcatc aag aag acc gag 1519 Leu Val Thr Glu His Ala Gln Leu Val Gln Val IleLys Lys Thr Glu 440 445 450 tcc gac gca gcg ctg cac cca ctg ttg caa gagatc tac aga gac atg 1567 Ser Asp Ala Ala Leu His Pro Leu Leu Gln Glu IleTyr Arg Asp Met 455 460 465 tac tga tctttcctga gatggcaggc cattaccactgttcagggac ctccgaggcc 1623 Tyr * tgcggcccca tacaggagag cagggatttgcacagagggc ctccctccta cgcttgggga 1683 tgaagagggc tgagcgtagg taatgcgggctctccccaca tcctttctga atgggcactt 1743 ctaagactac ctgctaccga aatgggggtgatcggaggct aataggattc agacagtgac 1803 agacaacggc agtccccagt ctggtcttaaccggcccaat gttaatcaat gcacagcact 1863 ctacgttgcg tttataattc gccattaattaacgggtaac ctcgaagtct gagcggtctg 1923 ttcccttcct gccacccttc tggctatgtgcactctctta aatccctgaa aactaatctg 1983 cactttttaa cctttgaaaa cctacaagtcaaggtgtggc ccaaggttag ccatttaaat 2043 gtggcaaaaa aaaaaaaaaa aaaaaaaaaaaaaaaaaa 2081 12 468 PRT Mus musculus 12 Met Val Asp Thr Glu Ser Pro IleCys Pro Leu Ser Pro Leu Glu Ala 1 5 10 15 Asp Asp Leu Glu Ser Pro LeuSer Glu Glu Phe Leu Gln Glu Met Gly 20 25 30 Asn Ile Gln Glu Ile Ser GlnSer Ile Gly Glu Glu Ser Ser Gly Ser 35 40 45 Phe Gly Phe Ala Asp Tyr GlnTyr Leu Gly Ser Cys Pro Gly Ser Glu 50 55 60 Gly Ser Val Ile Thr Asp ThrLeu Ser Pro Arg Ser Ser Pro Ser Ser 65 70 75 80 Val Ser Cys Pro Val IlePro Ala Ser Thr Asp Glu Ser Pro Gly Ser 85 90 95 Ala Leu Asn Ile Glu CysArg Ile Cys Gly Asp Lys Ala Ser Gly Tyr 100 105 110 His Tyr Gly Val HisAla Cys Glu Gly Cys Lys Gly Phe Phe Arg Arg 115 120 125 Thr Ile Arg LeuLys Leu Val Tyr Asp Lys Cys Asp Arg Ser Cys Lys 130 135 140 Ile Gln LysLys Asn Arg Asn Lys Cys Gln Tyr Cys Arg Phe His Lys 145 150 155 160 CysLeu Ser Val Gly Met Ser His Asn Ala Ile Arg Phe Gly Arg Met 165 170 175Pro Arg Ser Glu Lys Ala Lys Leu Lys Ala Glu Ile Leu Thr Cys Glu 180 185190 His Asp Leu Lys Asp Ser Glu Thr Ala Asp Leu Lys Ser Leu Gly Lys 195200 205 Arg Ile His Glu Ala Tyr Leu Lys Asn Phe Asn Met Asn Lys Val Lys210 215 220 Ala Arg Val Ile Leu Ala Gly Lys Thr Ser Asn Asn Pro Pro PheVal 225 230 235 240 Ile His Asp Met Glu Thr Leu Cys Met Ala Glu Lys ThrLeu Val Ala 245 250 255 Lys Met Val Ala Asn Gly Val Glu Asp Lys Glu AlaGlu Val Arg Phe 260 265 270 Phe His Cys Cys Gln Cys Met Ser Val Glu ThrVal Thr Glu Leu Thr 275 280 285 Glu Phe Ala Lys Ala Ile Pro Gly Phe AlaAsn Leu Asp Leu Asn Asp 290 295 300 Gln Val Thr Leu Leu Lys Tyr Gly ValTyr Glu Ala Ile Phe Thr Met 305 310 315 320 Leu Ser Ser Leu Met Asn LysAsp Gly Met Leu Ile Ala Tyr Gly Asn 325 330 335 Gly Phe Ile Thr Arg GluPhe Leu Lys Asn Leu Arg Lys Pro Phe Cys 340 345 350 Asp Ile Met Glu ProLys Phe Asp Phe Ala Met Lys Phe Asn Ala Leu 355 360 365 Glu Leu Asp AspSer Asp Ile Ser Leu Phe Val Ala Ala Ile Ile Cys 370 375 380 Cys Gly AspArg Pro Gly Leu Leu Asn Ile Gly Tyr Ile Glu Lys Leu 385 390 395 400 GlnGlu Gly Ile Val His Val Leu Lys Leu His Leu Gln Ser Asn His 405 410 415Pro Asp Asp Thr Phe Leu Phe Pro Lys Leu Leu Gln Lys Met Val Asp 420 425430 Leu Arg Gln Leu Val Thr Glu His Ala Gln Leu Val Gln Val Ile Lys 435440 445 Lys Thr Glu Ser Asp Ala Ala Leu His Pro Leu Leu Gln Glu Ile Tyr450 455 460 Arg Asp Met Tyr 465 13 1323 DNA Mus musculus CDS(1)...(1323) GeneBank U10375 1994-07-22 13 atg gaa cag cca cag gag gagacc cct gag gcc cgg gaa gag gag aaa 48 Met Glu Gln Pro Gln Glu Glu ThrPro Glu Ala Arg Glu Glu Glu Lys 1 5 10 15 gag gaa gtg gcc atg ggt gacgga gcc ccg gag ctc aat ggg gga cca 96 Glu Glu Val Ala Met Gly Asp GlyAla Pro Glu Leu Asn Gly Gly Pro 20 25 30 gaa cac acg ctt cct tcc agc agctgt gca gac ctc tcc cag aat tcc 144 Glu His Thr Leu Pro Ser Ser Ser CysAla Asp Leu Ser Gln Asn Ser 35 40 45 tcc cct tcc tcc ctg ctg gac cag ctgcag atg ggc tgt gat ggg gcc 192 Ser Pro Ser Ser Leu Leu Asp Gln Leu GlnMet Gly Cys Asp Gly Ala 50 55 60 tca ggc ggc agc ctc aac atg gaa tgt cgggtg tgc ggg gac aag gcc 240 Ser Gly Gly Ser Leu Asn Met Glu Cys Arg ValCys Gly Asp Lys Ala 65 70 75 80 tcg ggc ttc cac tac ggg gtc cac gcg tgcgag ggg tgc aag ggc ttc 288 Ser Gly Phe His Tyr Gly Val His Ala Cys GluGly Cys Lys Gly Phe 85 90 95 ttc cgc cgg aca atc cgc atg aag ctc gag tatgag aag tgc gat cgg 336 Phe Arg Arg Thr Ile Arg Met Lys Leu Glu Tyr GluLys Cys Asp Arg 100 105 110 atc tgc aag atc cag aag aag aac cgc aac aagtgt cag tac tgc cgc 384 Ile Cys Lys Ile Gln Lys Lys Asn Arg Asn Lys CysGln Tyr Cys Arg 115 120 125 ttc cag aag tgc ctg gca ctc ggc atg tcg cacaac gct atc cgc ttt 432 Phe Gln Lys Cys Leu Ala Leu Gly Met Ser His AsnAla Ile Arg Phe 130 135 140 gga cgg atg ccg gac ggc gag aag agg aag ctggtg gcg ggg ctg act 480 Gly Arg Met Pro Asp Gly Glu Lys Arg Lys Leu ValAla Gly Leu Thr 145 150 155 160 gcc agc gag ggg tgc cag cac aac ccc cagctg gcc gac ctg aag gcc 528 Ala Ser Glu Gly Cys Gln His Asn Pro Gln LeuAla Asp Leu Lys Ala 165 170 175 ttc tct aag cac atc tac aac gcc tac ctgaaa aac ttc aac atg acc 576 Phe Ser Lys His Ile Tyr Asn Ala Tyr Leu LysAsn Phe Asn Met Thr 180 185 190 aaa aag aag gcc cgg agc atc ctc acc ggcaag tcc agc cac aac gca 624 Lys Lys Lys Ala Arg Ser Ile Leu Thr Gly LysSer Ser His Asn Ala 195 200 205 ccc ttt gtc atc cac gac atc gag aca ctgtgg cag gca gag aag ggc 672 Pro Phe Val Ile His Asp Ile Glu Thr Leu TrpGln Ala Glu Lys Gly 210 215 220 ctg gtg tgg aaa cag ctg gtg aac ggg ctgccg ccc tac aac gag atc 720 Leu Val Trp Lys Gln Leu Val Asn Gly Leu ProPro Tyr Asn Glu Ile 225 230 235 240 agt gtg cac gtg ttc tac cgc tgc cagtcc acc aca gtg gag aca gtc 768 Ser Val His Val Phe Tyr Arg Cys Gln SerThr Thr Val Glu Thr Val 245 250 255 cga gag ctc acc gag ttc gcc aag aacatc ccc aac ttc agc agc ctc 816 Arg Glu Leu Thr Glu Phe Ala Lys Asn IlePro Asn Phe Ser Ser Leu 260 265 270 ttc ctc aat gac cag gtg acc ctc ctcaag tat ggc gtg cac gag gcc 864 Phe Leu Asn Asp Gln Val Thr Leu Leu LysTyr Gly Val His Glu Ala 275 280 285 atc ttt gcc atg ctg gcc tcc atc gtcaac aaa gac ggg ctg ctg gtg 912 Ile Phe Ala Met Leu Ala Ser Ile Val AsnLys Asp Gly Leu Leu Val 290 295 300 gcc aac ggc agt ggc ttc gtc acc cacgag ttc ttg cga agt ctc cgc 960 Ala Asn Gly Ser Gly Phe Val Thr His GluPhe Leu Arg Ser Leu Arg 305 310 315 320 aag ccc ttc agt gac atc att gagccc aag ttc gag ttt gct gtc aag 1008 Lys Pro Phe Ser Asp Ile Ile Glu ProLys Phe Glu Phe Ala Val Lys 325 330 335 ttc aat gcg ctg gag ctc gat gacagt gac ctg gcg ctc ttc atc gcg 1056 Phe Asn Ala Leu Glu Leu Asp Asp SerAsp Leu Ala Leu Phe Ile Ala 340 345 350 gcc atc att ctg tgt gga gac cggcca ggc ctc atg aat gtg ccc cag 1104 Ala Ile Ile Leu Cys Gly Asp Arg ProGly Leu Met Asn Val Pro Gln 355 360 365 gta gaa gcc atc cag gac acc attctg cgg gct cta gaa ttc cat ctg 1152 Val Glu Ala Ile Gln Asp Thr Ile LeuArg Ala Leu Glu Phe His Leu 370 375 380 cag gtc aac cac cct gac agc cagtac ctc ttc ccc aag ctg ctg cag 1200 Gln Val Asn His Pro Asp Ser Gln TyrLeu Phe Pro Lys Leu Leu Gln 385 390 395 400 aag atg gca gac ctg cgg cagctg gtc act gag cat gcc cag atg atg 1248 Lys Met Ala Asp Leu Arg Gln LeuVal Thr Glu His Ala Gln Met Met 405 410 415 cag tgg cta aag aag acg gagagt gag acc ttg ctg cac ccc ctg ctc 1296 Gln Trp Leu Lys Lys Thr Glu SerGlu Thr Leu Leu His Pro Leu Leu 420 425 430 cag gaa atc tac aag gac atgtac taa 1323 Gln Glu Ile Tyr Lys Asp Met Tyr * 435 440 14 440 PRT Musmusculus 14 Met Glu Gln Pro Gln Glu Glu Thr Pro Glu Ala Arg Glu Glu GluLys 1 5 10 15 Glu Glu Val Ala Met Gly Asp Gly Ala Pro Glu Leu Asn GlyGly Pro 20 25 30 Glu His Thr Leu Pro Ser Ser Ser Cys Ala Asp Leu Ser GlnAsn Ser 35 40 45 Ser Pro Ser Ser Leu Leu Asp Gln Leu Gln Met Gly Cys AspGly Ala 50 55 60 Ser Gly Gly Ser Leu Asn Met Glu Cys Arg Val Cys Gly AspLys Ala 65 70 75 80 Ser Gly Phe His Tyr Gly Val His Ala Cys Glu Gly CysLys Gly Phe 85 90 95 Phe Arg Arg Thr Ile Arg Met Lys Leu Glu Tyr Glu LysCys Asp Arg 100 105 110 Ile Cys Lys Ile Gln Lys Lys Asn Arg Asn Lys CysGln Tyr Cys Arg 115 120 125 Phe Gln Lys Cys Leu Ala Leu Gly Met Ser HisAsn Ala Ile Arg Phe 130 135 140 Gly Arg Met Pro Asp Gly Glu Lys Arg LysLeu Val Ala Gly Leu Thr 145 150 155 160 Ala Ser Glu Gly Cys Gln His AsnPro Gln Leu Ala Asp Leu Lys Ala 165 170 175 Phe Ser Lys His Ile Tyr AsnAla Tyr Leu Lys Asn Phe Asn Met Thr 180 185 190 Lys Lys Lys Ala Arg SerIle Leu Thr Gly Lys Ser Ser His Asn Ala 195 200 205 Pro Phe Val Ile HisAsp Ile Glu Thr Leu Trp Gln Ala Glu Lys Gly 210 215 220 Leu Val Trp LysGln Leu Val Asn Gly Leu Pro Pro Tyr Asn Glu Ile 225 230 235 240 Ser ValHis Val Phe Tyr Arg Cys Gln Ser Thr Thr Val Glu Thr Val 245 250 255 ArgGlu Leu Thr Glu Phe Ala Lys Asn Ile Pro Asn Phe Ser Ser Leu 260 265 270Phe Leu Asn Asp Gln Val Thr Leu Leu Lys Tyr Gly Val His Glu Ala 275 280285 Ile Phe Ala Met Leu Ala Ser Ile Val Asn Lys Asp Gly Leu Leu Val 290295 300 Ala Asn Gly Ser Gly Phe Val Thr His Glu Phe Leu Arg Ser Leu Arg305 310 315 320 Lys Pro Phe Ser Asp Ile Ile Glu Pro Lys Phe Glu Phe AlaVal Lys 325 330 335 Phe Asn Ala Leu Glu Leu Asp Asp Ser Asp Leu Ala LeuPhe Ile Ala 340 345 350 Ala Ile Ile Leu Cys Gly Asp Arg Pro Gly Leu MetAsn Val Pro Gln 355 360 365 Val Glu Ala Ile Gln Asp Thr Ile Leu Arg AlaLeu Glu Phe His Leu 370 375 380 Gln Val Asn His Pro Asp Ser Gln Tyr LeuPhe Pro Lys Leu Leu Gln 385 390 395 400 Lys Met Ala Asp Leu Arg Gln LeuVal Thr Glu His Ala Gln Met Met 405 410 415 Gln Trp Leu Lys Lys Thr GluSer Glu Thr Leu Leu His Pro Leu Leu 420 425 430 Gln Glu Ile Tyr Lys AspMet Tyr 435 440 15 1827 DNA Homo Sapien CDS (292)...(1683) GeneBankXM_053680 2002-05-08 15 gtagcggtga cggcggcggc ggcggcggcg gcagcattatgcgtgattac tgacaggcac 60 cagctgctgc cgccacagcc gtctcaaacg cactatgtggactctccgat ctagaggcag 120 attcctgact aatcccagag ggctggccca gcctgtgctccccgggctgc taggaagcga 180 tgaccactct tgttagccca agttgaagaa agccgggctgtgcctgggag ccgagagagg 240 cggtaatatt tagaagctgc acaggagagg aacatgaactgacgagtaaa c atg tat 297 Met Tyr 1 gga aat tat tct cac ttc atg aag tttccc gca ggc tat gga ggc tcc 345 Gly Asn Tyr Ser His Phe Met Lys Phe ProAla Gly Tyr Gly Gly Ser 5 10 15 cct ggc cac act ggc tct aca tcc atg agccca tca gca gcc ttg tcc 393 Pro Gly His Thr Gly Ser Thr Ser Met Ser ProSer Ala Ala Leu Ser 20 25 30 aca ggg aag cca atg gac agc cac ccc agc tacaca gat acc cca gtg 441 Thr Gly Lys Pro Met Asp Ser His Pro Ser Tyr ThrAsp Thr Pro Val 35 40 45 50 agt gcc cca cgg act ctg agt gca gtg ggg accccc ctc aat gcc ctg 489 Ser Ala Pro Arg Thr Leu Ser Ala Val Gly Thr ProLeu Asn Ala Leu 55 60 65 ggc tct cca tat cga gtc atc acc tct gcc atg ggccca ccc tca gga 537 Gly Ser Pro Tyr Arg Val Ile Thr Ser Ala Met Gly ProPro Ser Gly 70 75 80 gca ctt gca gcg cct cca gga atc aac ttg gtt gcc ccaccc agc tct 585 Ala Leu Ala Ala Pro Pro Gly Ile Asn Leu Val Ala Pro ProSer Ser 85 90 95 cag cta aat gtg gtc aac agt gtc agc agt tca gag gac atcaag ccc 633 Gln Leu Asn Val Val Asn Ser Val Ser Ser Ser Glu Asp Ile LysPro 100 105 110 tta cca ggg ctt ccc ggg att gga aac atg aac tac cca tccacc agc 681 Leu Pro Gly Leu Pro Gly Ile Gly Asn Met Asn Tyr Pro Ser ThrSer 115 120 125 130 ccc gga tct ctg gtt aaa cac atc tgt gcc atc tgt ggagac aga tcc 729 Pro Gly Ser Leu Val Lys His Ile Cys Ala Ile Cys Gly AspArg Ser 135 140 145 tca gga aag cac tac ggg gta tac agt tgt gaa ggc tgcaaa ggg ttc 777 Ser Gly Lys His Tyr Gly Val Tyr Ser Cys Glu Gly Cys LysGly Phe 150 155 160 ttc aag agg acg ata agg aag gac ctc atc tac acg tgtcgg gat aat 825 Phe Lys Arg Thr Ile Arg Lys Asp Leu Ile Tyr Thr Cys ArgAsp Asn 165 170 175 aaa gac tgc ctc att gac aag cgt cag cgc aac cgc tgccag tac tgt 873 Lys Asp Cys Leu Ile Asp Lys Arg Gln Arg Asn Arg Cys GlnTyr Cys 180 185 190 cgc tat cag aag tgc ctt gtc atg ggc atg aag agg gaagct gtg caa 921 Arg Tyr Gln Lys Cys Leu Val Met Gly Met Lys Arg Glu AlaVal Gln 195 200 205 210 gaa gaa aga cag agg agc cga gag cga gct gag agtgag gca gaa tgt 969 Glu Glu Arg Gln Arg Ser Arg Glu Arg Ala Glu Ser GluAla Glu Cys 215 220 225 gct acc agt ggt cat gaa gac atg cct gtg gag aggatt cta gaa gct 1017 Ala Thr Ser Gly His Glu Asp Met Pro Val Glu Arg IleLeu Glu Ala 230 235 240 gaa ctt gct gtt gaa cca aag aca gaa tcc tat ggtgac atg aat atg 1065 Glu Leu Ala Val Glu Pro Lys Thr Glu Ser Tyr Gly AspMet Asn Met 245 250 255 gag aac tcg aca aat gac cct gtt acc aac ata tgtcat gct gct gac 1113 Glu Asn Ser Thr Asn Asp Pro Val Thr Asn Ile Cys HisAla Ala Asp 260 265 270 aag cag ctt ttc acc ctc gtt gaa tgg gcc aag cgtatt ccc cac ttc 1161 Lys Gln Leu Phe Thr Leu Val Glu Trp Ala Lys Arg IlePro His Phe 275 280 285 290 tct gac ctc acc ttg gag gac cag gtc att ttgctt cgg gca ggg tgg 1209 Ser Asp Leu Thr Leu Glu Asp Gln Val Ile Leu LeuArg Ala Gly Trp 295 300 305 aat gaa ttg ctg att gcc tct ttc tcc cac cgctca gtt tcc gtg cag 1257 Asn Glu Leu Leu Ile Ala Ser Phe Ser His Arg SerVal Ser Val Gln 310 315 320 gat ggc atc ctt ctg gcc acg ggt tta cat gtccac cgg agc agt gcc 1305 Asp Gly Ile Leu Leu Ala Thr Gly Leu His Val HisArg Ser Ser Ala 325 330 335 cac agt gct ggg gtc ggc tcc atc ttt gac agagtc cta act gag ctg 1353 His Ser Ala Gly Val Gly Ser Ile Phe Asp Arg ValLeu Thr Glu Leu 340 345 350 gtt tcc aaa atg aaa gac atg cag atg gac aagtcg gaa ctg gga tgc 1401 Val Ser Lys Met Lys Asp Met Gln Met Asp Lys SerGlu Leu Gly Cys 355 360 365 370 ctg cga gcc att gta ctc ttt aac cca gatgcc aag ggc ctg tcc aac 1449 Leu Arg Ala Ile Val Leu Phe Asn Pro Asp AlaLys Gly Leu Ser Asn 375 380 385 ccc tct gag gtg gag act ctg cga gag aaggtt tat gcc acc ctt gag 1497 Pro Ser Glu Val Glu Thr Leu Arg Glu Lys ValTyr Ala Thr Leu Glu 390 395 400 gcc tac acc aag cag aag tat ccg gaa cagcca ggc agg ttt gcc aag 1545 Ala Tyr Thr Lys Gln Lys Tyr Pro Glu Gln ProGly Arg Phe Ala Lys 405 410 415 ctg ctg ctg cgc ctc cca gct ctg cgt tccatt ggc ttg aaa tgc ctg 1593 Leu Leu Leu Arg Leu Pro Ala Leu Arg Ser IleGly Leu Lys Cys Leu 420 425 430 gag cac ctc ttc ttc ttc aag ctc atc ggggac acc ccc att gac acc 1641 Glu His Leu Phe Phe Phe Lys Leu Ile Gly AspThr Pro Ile Asp Thr 435 440 445 450 ttc ctc atg gag atg ttg gag acc ccgctg cag atc acc tga 1683 Phe Leu Met Glu Met Leu Glu Thr Pro Leu Gln IleThr * 455 460 gccccaccag ccacagcctc cccacccagg atgacccctg ggcaggtgtgtgtggacccc 1743 caccctgcac tttcctccac ctcccaccct gacccccttc ctgtccccaaaatgtgatgc 1803 ttataataaa gaaaaccttt ctac 1827 16 463 PRT Homo Sapien16 Met Tyr Gly Asn Tyr Ser His Phe Met Lys Phe Pro Ala Gly Tyr Gly 1 510 15 Gly Ser Pro Gly His Thr Gly Ser Thr Ser Met Ser Pro Ser Ala Ala 2025 30 Leu Ser Thr Gly Lys Pro Met Asp Ser His Pro Ser Tyr Thr Asp Thr 3540 45 Pro Val Ser Ala Pro Arg Thr Leu Ser Ala Val Gly Thr Pro Leu Asn 5055 60 Ala Leu Gly Ser Pro Tyr Arg Val Ile Thr Ser Ala Met Gly Pro Pro 6570 75 80 Ser Gly Ala Leu Ala Ala Pro Pro Gly Ile Asn Leu Val Ala Pro Pro85 90 95 Ser Ser Gln Leu Asn Val Val Asn Ser Val Ser Ser Ser Glu Asp Ile100 105 110 Lys Pro Leu Pro Gly Leu Pro Gly Ile Gly Asn Met Asn Tyr ProSer 115 120 125 Thr Ser Pro Gly Ser Leu Val Lys His Ile Cys Ala Ile CysGly Asp 130 135 140 Arg Ser Ser Gly Lys His Tyr Gly Val Tyr Ser Cys GluGly Cys Lys 145 150 155 160 Gly Phe Phe Lys Arg Thr Ile Arg Lys Asp LeuIle Tyr Thr Cys Arg 165 170 175 Asp Asn Lys Asp Cys Leu Ile Asp Lys ArgGln Arg Asn Arg Cys Gln 180 185 190 Tyr Cys Arg Tyr Gln Lys Cys Leu ValMet Gly Met Lys Arg Glu Ala 195 200 205 Val Gln Glu Glu Arg Gln Arg SerArg Glu Arg Ala Glu Ser Glu Ala 210 215 220 Glu Cys Ala Thr Ser Gly HisGlu Asp Met Pro Val Glu Arg Ile Leu 225 230 235 240 Glu Ala Glu Leu AlaVal Glu Pro Lys Thr Glu Ser Tyr Gly Asp Met 245 250 255 Asn Met Glu AsnSer Thr Asn Asp Pro Val Thr Asn Ile Cys His Ala 260 265 270 Ala Asp LysGln Leu Phe Thr Leu Val Glu Trp Ala Lys Arg Ile Pro 275 280 285 His PheSer Asp Leu Thr Leu Glu Asp Gln Val Ile Leu Leu Arg Ala 290 295 300 GlyTrp Asn Glu Leu Leu Ile Ala Ser Phe Ser His Arg Ser Val Ser 305 310 315320 Val Gln Asp Gly Ile Leu Leu Ala Thr Gly Leu His Val His Arg Ser 325330 335 Ser Ala His Ser Ala Gly Val Gly Ser Ile Phe Asp Arg Val Leu Thr340 345 350 Glu Leu Val Ser Lys Met Lys Asp Met Gln Met Asp Lys Ser GluLeu 355 360 365 Gly Cys Leu Arg Ala Ile Val Leu Phe Asn Pro Asp Ala LysGly Leu 370 375 380 Ser Asn Pro Ser Glu Val Glu Thr Leu Arg Glu Lys ValTyr Ala Thr 385 390 395 400 Leu Glu Ala Tyr Thr Lys Gln Lys Tyr Pro GluGln Pro Gly Arg Phe 405 410 415 Ala Lys Leu Leu Leu Arg Leu Pro Ala LeuArg Ser Ile Gly Leu Lys 420 425 430 Cys Leu Glu His Leu Phe Phe Phe LysLeu Ile Gly Asp Thr Pro Ile 435 440 445 Asp Thr Phe Leu Met Glu Met LeuGlu Thr Pro Leu Gln Ile Thr 450 455 460 17 1330 DNA Homo Sapien CDS(97)...(837) GeneBank XM_042579 2002-02-06 17 ttggggttgt gctccagggatggcctttca catagactgc agtgtaaatg acagcctctg 60 gaatgtgcat tgcagggccttgcttagtgg taggga atg att tcc atc act tct 114 Met Ile Ser Ile Thr Ser 15 gtg aca ttc tgc ttc cca ata agt ctt cct gtg act tcc cta ttt ccc 162Val Thr Phe Cys Phe Pro Ile Ser Leu Pro Val Thr Ser Leu Phe Pro 10 15 20cca tcc cag att aac tca aca gtg tca ctc cct ggg ggt ggg tct ggc 210 ProSer Gln Ile Asn Ser Thr Val Ser Leu Pro Gly Gly Gly Ser Gly 25 30 35 ccccct gaa gat gtg aag cca cca gtc tta ggg gtc cgg ggc ctg cac 258 Pro ProGlu Asp Val Lys Pro Pro Val Leu Gly Val Arg Gly Leu His 40 45 50 tgt ccaccc cct cca ggt ggc cct ggg gct ggc aaa cgg cta tgt gca 306 Cys Pro ProPro Pro Gly Gly Pro Gly Ala Gly Lys Arg Leu Cys Ala 55 60 65 70 atc tgcggg gac aga agc tca ggc aaa cac tac ggg gtt tac agc tgt 354 Ile Cys GlyAsp Arg Ser Ser Gly Lys His Tyr Gly Val Tyr Ser Cys 75 80 85 gag ggt tgcaag ggc ttc ttc aaa cgc acc atc cgc aaa gac ctt aca 402 Glu Gly Cys LysGly Phe Phe Lys Arg Thr Ile Arg Lys Asp Leu Thr 90 95 100 tac tct tgccgg gac aac aaa gac tgc aca gtg gac aag cgc cag cgg 450 Tyr Ser Cys ArgAsp Asn Lys Asp Cys Thr Val Asp Lys Arg Gln Arg 105 110 115 aac cgc tgtcag tac tgc cgc tat cag aag tgc ctg gcc act ggc atg 498 Asn Arg Cys GlnTyr Cys Arg Tyr Gln Lys Cys Leu Ala Thr Gly Met 120 125 130 aag agg gaggcg gta cag gag gag cgt cag cgg gga aag gac aag gat 546 Lys Arg Glu AlaVal Gln Glu Glu Arg Gln Arg Gly Lys Asp Lys Asp 135 140 145 150 ggg gatggg gag ggg gct ggg gga gcc ccc gag gag atg cct gtg gac 594 Gly Asp GlyGlu Gly Ala Gly Gly Ala Pro Glu Glu Met Pro Val Asp 155 160 165 agg atcctg gag gca gag ctt gct gtg gaa cag aag agt gac cag ggc 642 Arg Ile LeuGlu Ala Glu Leu Ala Val Glu Gln Lys Ser Asp Gln Gly 170 175 180 gtt gagggt cct ggg gga acc ggg ggt agc ggc agc agc gtg agt gtt 690 Val Glu GlyPro Gly Gly Thr Gly Gly Ser Gly Ser Ser Val Ser Val 185 190 195 ggg gtcaat cca ctc tcc ttc gtg atg ggg gtt ggg gga ggc agt cta 738 Gly Val AsnPro Leu Ser Phe Val Met Gly Val Gly Gly Gly Ser Leu 200 205 210 ggt ctgttc tac atc ccc tcc ccc tcc ttt ccc ctc ata acc ttc cta 786 Gly Leu PheTyr Ile Pro Ser Pro Ser Phe Pro Leu Ile Thr Phe Leu 215 220 225 230 acacta ctt ggg act gga ggt gct gcc aaa caa ggt ctt tca aac atc 834 Thr LeuLeu Gly Thr Gly Gly Ala Ala Lys Gln Gly Leu Ser Asn Ile 235 240 245 tgaggtggatgtg atagctcctt ctgtctccac tccccaaaca acccactggc 887 * agaaccataggcatgtccca aataaataat tgtttgcact aatgccagaa gagaagactc 947 acttacagggattggtttgg atggggctca caggaagact atatgtaagg agggggtgtc 1007 aaaagcctcttacaaggggg ctcccagcat atctcaaaat cttccataac tcttaccccc 1067 gtcccctgcagccaaatgac cctgtgacta acatctgtca ggcagctgac aaacagctat 1127 tcacgcttgttgagtgggcg aagaggatcc cacacttttc ctccttgcct ctggatgatc 1187 aggtcatattgctgcgggca ggtcagtgac cttggatccc tttgacttct tgacatttga 1247 cccctctttgacttcccgat ctttagtgac cccagtggcc ttaccttgcg tacccaggga 1307 gccaaacttgctgacctcgc cac 1330 18 246 PRT Homo Sapien 18 Met Ile Ser Ile Thr SerVal Thr Phe Cys Phe Pro Ile Ser Leu Pro 1 5 10 15 Val Thr Ser Leu PhePro Pro Ser Gln Ile Asn Ser Thr Val Ser Leu 20 25 30 Pro Gly Gly Gly SerGly Pro Pro Glu Asp Val Lys Pro Pro Val Leu 35 40 45 Gly Val Arg Gly LeuHis Cys Pro Pro Pro Pro Gly Gly Pro Gly Ala 50 55 60 Gly Lys Arg Leu CysAla Ile Cys Gly Asp Arg Ser Ser Gly Lys His 65 70 75 80 Tyr Gly Val TyrSer Cys Glu Gly Cys Lys Gly Phe Phe Lys Arg Thr 85 90 95 Ile Arg Lys AspLeu Thr Tyr Ser Cys Arg Asp Asn Lys Asp Cys Thr 100 105 110 Val Asp LysArg Gln Arg Asn Arg Cys Gln Tyr Cys Arg Tyr Gln Lys 115 120 125 Cys LeuAla Thr Gly Met Lys Arg Glu Ala Val Gln Glu Glu Arg Gln 130 135 140 ArgGly Lys Asp Lys Asp Gly Asp Gly Glu Gly Ala Gly Gly Ala Pro 145 150 155160 Glu Glu Met Pro Val Asp Arg Ile Leu Glu Ala Glu Leu Ala Val Glu 165170 175 Gln Lys Ser Asp Gln Gly Val Glu Gly Pro Gly Gly Thr Gly Gly Ser180 185 190 Gly Ser Ser Val Ser Val Gly Val Asn Pro Leu Ser Phe Val MetGly 195 200 205 Val Gly Gly Gly Ser Leu Gly Leu Phe Tyr Ile Pro Ser ProSer Phe 210 215 220 Pro Leu Ile Thr Phe Leu Thr Leu Leu Gly Thr Gly GlyAla Ala Lys 225 230 235 240 Gln Gly Leu Ser Asn Ile 245

What is claimed is:
 1. A compound that has formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: X¹, X² and X³ are selected from (i) or (ii) as follows: (i) X¹, X² and X³ are each independently S, O or NR⁵; or (ii) X¹ is —CR⁸═CR⁹—, where R⁸ and R⁹ are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ and C(═J)R¹³; and X² and X³ are each independently S, O or NR⁵; R¹ is substituted or unsubstituted alkyl; R² is substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaralkyl, or substituted or unsubstituted heterocyclylalkyl; R³ is substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; A and G are selected from (i), (ii) or (iii) as follows: (i) A and G are each independently selected from hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, hydroxycarbonyl, and substituted or unsubstituted alkylcarbonyl, where the substituents, when present, are each selected independently from Q¹, with the proviso that when R¹ is Et, X¹ and X² are S, X³ is O, R³ is 3-methylphenyl, R² is allyl, and D and E form a bond, then A and G are not both methyl; or (ii) A and G together form substituted or unsubstituted alkylene, or substituted or unsubstituted azaalkylene, where the substituents, when present, are each selected independently from Q¹; or (iii) A and G together form substituted butadienyl, where there are 1 to 4 substituents selected from Q¹, with the provisos that (a) when X¹ and X² are S and X³ is O, then the resulting benzothiazolyl group is not mono-substituted at the 5-position with methoxy or chloro or at the 6-position with methoxy, and (b) when X¹ is —CR⁸═CR⁹—, X² is S and X³ is O, then the resulting quinolyl group is not mono-substituted at the 6-position with methoxy or methyl; D and E are each hydrogen, or together form a bond; and R⁵ is hydrogen, substituted or unsubstituted alkyl substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹⁴R¹⁵ or C(═J)R¹³; R¹⁰ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl or C(═J)R¹³; J is O, S or NR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ and R¹⁶ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl moieties of R¹, R², R³, R⁵, R¹⁰, R¹³, A and G, when substituted, are substituted with one or more substituents each independently selected from Q¹, where Q¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino, hydroxyimino, alkoxyimino, aralkoxyimino, arylazo, haloalkylcarbonylamino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups, which substitute the same atom, together form alkylene; each Q¹ is independently unsubstituted or substituted with one or more substituents each independently selected from Q²; each Q² is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy where y is 1 or 2; or two Q² groups, which substitute the same atom, together form alkylene; R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹ together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹.
 2. The compound of claim 1, wherein X¹ is S.
 3. The compound of claim 1, wherein X² is S.
 4. The compound of claim 1, wherein X³ is O.
 5. The compound of claim 1 that has formulae II:


6. The compound of claim 1, wherein R¹ is unsubstituted alkyl.
 7. The compound of claim 1, wherein R¹ is methyl.
 8. The compound of claim 1, wherein R² is benzyl, phenyl, allyl, ethyl, butyl, cyclohexyl, propyl, 3-pyridylmethyl, 2-furylmethyl, 4-methoxycarbonylbenzyl, 4-hydroxycarbonylbenzyl, 2-phenethyl, 2-pyridylmethyl, 4-pyridylmethyl or 2-(4-morpholinyl)ethyl.
 9. The compound of claim 1, wherein R² is benzyl, 3-pyridylmethyl or 2-furylmethyl.
 10. The compound of claim 1, wherein R³ is substituted or unsubstituted quinolyl, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted isoquinolyl, substituted or unsubstituted pyridyl, or substituted or unsubstituted indazolyl.
 11. The compound of claim 1, wherein R³ is substituted or unsubstituted phenyl.
 12. The compound of claim 1, wherein R³ is substituted with 0 to 5 substituents selected from ethylamino, cyano, cyclohexyl, hydroxy, methoxy, dimethylamino, amino, 4-morpholinyl, methylamino, isopropylamino, benzyloxy, methyl, isopropyl, nitro, trifluoromethyl, methylcarbonyl, chloro, propyl, ethoxy, methylcarbonylamino, aminocarbonyl, methoxycarbonyl, butylamino, benzylamino, cyclopentylamino, 1-pyrrolidinylamino, pyrrolidinyl, t-butylamino, 2,2,2-trifluoroethylamino, piperidinyl, trifluoromethoxy, hydroxycarbonyl, aminosulfonyl, methylcarbonylaminosulfonyl, trifluoromethylcarbonylamino and t-butoxycarbonyl, or any two substituents, which substitute atoms in a 1,2 arrangement, together form methylenedioxy.
 13. The compound of claim 1, wherein R³ is 5-quinolyl, 2-ethylamino-5-cyanophenyl, 4-cyclohexylphenyl, 2-hydroxy-1-naphthyl, 6-quinolyl, 3-methoxyphenyl, 4-dimethylaminophenyl, 4-aminophenyl, 4-(4-morpholinyl)phenyl, 2-methylamino-5-cyanophenyl, 2-dimethylamino-5-cyanophenyl, 2-ethylaminophenyl, 3-cyanophenyl, 2-aminophenyl, 2-isopropylamino-5-cyanophenyl, 4-benzyloxyphenyl, 2-methyl-4-hydroxy-5-isopropylphenyl, 2-ethylamino-5-nitrophenyl, 3-trifluoromethylphenyl, 3-methylcarbonylphenyl, 3-chlorophenyl, 2-propylphenyl, 2-ethoxyphenyl, 3-methylcarbonylaminophenyl, 3-aminocarbonylphenyl, 3-methoxycarbonylphenyl, 8-quinolyl, 8-hydroxy-5-quinolyl, 2-butylamino-5-cyanophenyl, 2-benzylamino-5-cyanophenyl, 2-cyclopentylamino-5-cyanophenyl, 2-(1-pyrrolidinyl)amino-5-cyanophenyl, 5-isoquinolyl, 1-isoquinolyl, 4-methylcarbonylaminophenyl, 2-t-butylamino-5-cyanophenyl, 2-(2,2,2-trifluoroethyl)amino-5-cyanophenyl, 2-piperidinyl-5-cyanophenyl, 4-methylcarbonylphenyl, 4-aminocarbonylphenyl, 1-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 2-ethoxy-5-methylcarbonylaminophenyl, 4-pyridyl, 4-methoxycarbonylphenyl, 4-trifluoromethoxyphenyl, 5-indazolyl, 4-(imidazol-1-yl)phenyl, 3,4-methylenedioxyphenyl, 3-hydroxycarbonylphenyl, 2-ethylamino-5-methylcarbonylphenyl, 4-aminosulfonylphenyl, 4-methylcarbonylaminosulfonylphenyl, 3-methylcarbonylphenyl, 2-methylcarbonylamino-5-pyridyl, 4-cyano-3-methylcarbonylaminophenyl, 2-methylamino-5-methylcarbonylphenyl, 4-trifluoromethylcarbonylaminophenyl, 2-ethylamino-5-methoxycarbonylphenyl, 2-hydroxycarbonylphenyl or 2-ethylamino-5-t-butoxycarbonylphenyl.
 14. The compound of claim 1, wherein A and G are each independently selected from hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted methyl and substituted or unsubstituted methylcarbonyl, or A and G together from substituted or unsubstituted butylene, or substituted or unsubstituted propylene.
 15. The compound of claim 1, wherein A and G are each independently selected from hydrogen, substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted methyl and substituted or unsubstituted methylcarbonyl, and are substituted with 0 to 4 substituents selected from chloro, bromo, methoxy, fluoro, ethoxy, nitro, trifluoromethyl, trifluoromethoxy, trifluoromethylcarbonylamino, dimethylaminocarbonyloxy, 2-(1-piperidinyl)ethoxy, 2-(1-methyl-4-piperazinyl)ethoxy, 2-(N-morpholinyl)ethoxy, 2-dimethylaminoethoxy, hydroxycarbonylmethoxy, methylcarbonylamino, hydroxy, ethylaminocarbonyloxy, methoxycarbonylmethoxy, aminocarbonylmethoxy, 2-hydroxyethoxy, 2-hydroxypropoxy, methyl, 2-chloroethylaminocarbonyloxy and 2-methylaminoethoxy.
 16. The compound of claim 1, wherein A and G are each independently selected from hydrogen, 4-nitrophenyl, 4-fluorophenyl, 4-chlorophenyl, 2-naphthyl, 4-bromophenyl, 2-methoxyphenyl, 3-fluorophenyl, 2,4-dimethoxyphenyl, 4-methylphenyl, 4-methoxyphenyl, methyl, phenyl and methylcarbonyl.
 17. The compound of claim 1, wherein D and E are each hydrogen or together form a bond.
 18. The compound of claim 1 that has formulae VI:

or a pharmaceutically acceptable derivative thereof, wherein R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently selected from hydrogen, ethylamino, cyano, cyclohexyl, hydroxy, methoxy, dimethylamino, amino, 4-morpholinyl, methylamino, isopropylamino, benzyloxy, methyl, isopropyl, nitro, trifluoromethyl, methylcarbonyl, chloro, propyl, ethoxy, methylcarbonylamino, aminocarbonyl, methoxycarbonyl, butylamino, benzylamino, cyclopentylamino, 1-pyrrolidinylamino, pyrrolidinyl, t-butylamino, 2,2,2-trifluoroethylamino, piperidinyl, trifluoromethoxy, hydroxycarbonyl, aminosulfonyl, methylcarbonylaminosulfonyl, trifluoromethylcarbonylamino and t-butoxycarbonyl, or any two substituents, which substitute atoms in a 1,2 arrangement, together form methylenedioxy.
 19. The compound of claim 1 that has formulae VII:

or a pharmaceutically acceptable derivative thereof, wherein R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently selected from hydrogen, ethylamino, cyano, cyclohexyl, hydroxy, methoxy, dimethylamino, amino, 4-morpholinyl, methylamino, isopropylamino, benzyloxy, methyl, isopropyl, nitro, trifluoromethyl, methylcarbonyl, chloro, propyl, ethoxy, methylcarbonylamino, aminocarbonyl, methoxycarbonyl, butylamino, benzylamino, cyclopentylamino, 1-pyrrolidinylamino, pyrrolidinyl, t-butylamino, 2,2,2-trifluoroethylamino, piperidinyl, trifluoromethoxy, hydroxycarbonyl, aminosulfonyl, methylcarbonylaminosulfonyl, trifluoromethylcarbonylamino and t-butoxycarbonyl, or any two substituents, which substitute atoms in a 1,2 arrangement, together form methylenedioxy.
 20. The compound of claim 1 that has formulae VIII:

or a pharmaceutically acceptable derivative thereof, wherein R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently selected from hydrogen, ethylamino, cyano, cyclohexyl, hydroxy, methoxy, dimethylamino, amino, 4-morpholinyl, methylamino, isopropylamino, benzyloxy, methyl, isopropyl, nitro, trifluoromethyl, methylcarbonyl, chloro, propyl, ethoxy, methylcarbonylamino, aminocarbonyl, methoxycarbonyl, butylamino, benzylamino, cyclopentylamino, 1-pyrrolidinylamino, pyrrolidinyl, t-butylamino, 2,2,2-trifluoroethylamino, piperidinyl, trifluoromethoxy, hydroxycarbonyl, aminosulfonyl, methylcarbonylaminosulfonyl, trifluoromethylcarbonylamino and t-butoxycarbonyl, or any two substituents, which substitute atoms in a 1,2 arrangement, together form methylenedioxy.
 21. The compound of claim 1 that has formulae IX:

or a pharmaceutically acceptable derivative thereof, wherein R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently selected from hydrogen, ethylamino, cyano, cyclohexyl, hydroxy, methoxy, dimethylamino, amino, 4-morpholinyl, methylamino, isopropylamino, benzyloxy, methyl, isopropyl, nitro, trifluoromethyl, methylcarbonyl, chloro, propyl, ethoxy, methylcarbonylamino, aminocarbonyl, methoxycarbonyl, butylamino, benzylamino, cyclopentylamino, 1-pyrrolidinylamino, pyrrolidinyl, t-butylamino, 2,2,2-trifluoroethylamino, piperidinyl, trifluoromethoxy, hydroxycarbonyl, aminosulfonyl, methylcarbonylaminosulfonyl, trifluoromethylcarbonylamino and t-butoxycarbonyl, or any two substituents, which substitute atoms in a 1,2 arrangement, together form methylenedioxy.
 22. The compound of claim 18, wherein R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently selected from (i) or (ii) as follows: (i) R²¹ is ethylamino; R¹⁸ is cyano; and R¹⁷, R¹⁹ and R²⁰ are each hydrogen; or (ii) R¹⁷ is ethylamino; R²⁰ is cyano; and R¹⁸, R¹⁹ and R²¹ are each hydrogen.
 23. A compound selected from: 3-benzyl-2-(4-methoxyphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-benzyl-2-(4-dimethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 2-(4-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-6-ylimino)-thiazolidine-4-one; 2-(2-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-benzyl-2-(4-benzyloxyphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-benzyl-2-(2-hydroxy- 1-naphthylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 3-benzyl-2-(4-hydroxy-5-isopropyl-2-methylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-benzyl-2-(2-ethylamino-5-nitrophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-[3-(trifluoromethyl)phenylimino]thiazolidine-4-one; 2-(3-acetylphenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-benzyl-2-(3-chlorophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-propylphenylimino)thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-5-ylimino)-thiazolidine-4-one; 3-benzyl-2-(2-ethoxyphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}acetamide; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzamide; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoic acid, methyl ester; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(pyridin-3-ylimino)thiazolidine-4-one; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethoxyphenyl}acetamide; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(pyridin-4-ylimino)thiazolidine-4-one; 4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoic acid, methyl ester; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-[4-(trifluoromethoxy)phenylimino]thiazolidine-4-one; 3-benzyl-2-(1H-indazol-5-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-benzyl-2-(4-imidazol-1-ylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 2-(benzo[1,3]dioxol-5-ylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoic acid; 3-benzyl-2-[2-(ethylamino)phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(methylamino)benzonitrile; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(isopropylamino)benzonitrile; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(dimethylamino)benzonitrile; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(tert-butylamino)benzonitrile; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(2,2,2-trifluoroethylamino)benzonitrile; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-piperidin-1-ylbenzonitrile; 2-[5-acetyl-2-(ethylamino)phenylimino]-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-morpholin-4-yl-phenylimino)thiazolidin-4-one; 3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(methylamino)benzonitrile; 4-dimethylamino-3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(isopropylamino)benzonitrile; 3-[3-butyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 3-benzyl-5-(3-methyl-3H-benzoxazol-2-ylidene)-2-(quinolin-5-ylimino)thiazolidin-4-one; N-[4-(3′-benzyl-3-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]-bithiazolyliden-2′-ylideneamino)phenyl]acetamide; 2′-[5-acetyl-2-(ethylamino)phenylimino]-3′-benzyl-3-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5]bithiazolyliden-4′-one; 3-(3′-benzyl-3-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazol-yliden-2′-ylideneamino)-4-(ethylamino)benzonitrile; N-[4-(3′-benzyl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)phenyl]acetamide; N-[4-(3′-benzyl-3-methyl-4′-oxo-[2,5′]bithiazolidinyliden-2′-ylideneamino)phenyl]acetamide; 3-(3′-benzyl-3,5-dimethyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]-bithiazolyliden-2′-ylideneamino)-4-(ethylamino)benzonitrile; 3-phenyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-benzylimino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(8-quinolyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(8-hydroxy-5-quinolyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(5-isoquinolyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(1-isoquinolyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-methylcarbonylamino)phenylimino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-methylcarbonyl)phenylimino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-aminocarbonyl)phenylimino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(1-naphthyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-naphthyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-pyridyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-aminosulfonyl)phenylimino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-methylcarbonylaminosulfonyl)phenylimino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(3-methylcarbonyl)phenylimino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-methylcarbonylamino-5-pyridyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-cyano-3-methylcarbonylaminophenyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-methylcarbonylphenyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-methylamino-5-methylcarbonylphenyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-trifluoromethylcarbonylaminophenyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-methoxycarbonylphenyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-hydroxycarbonylphenyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-tert-butoxycarbonylphenyl)imino-thiazolidine-4-one; 4-butylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-benzylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-cyclopentylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-pyrrolidinylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-pyrrolidinyl-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-cyclohexyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 3-allyl-5-(3-methyl-3H-benzothiazol-2-ylid ene)-2-(4-hydroxy-2-methyl-5-isopropylphenyl)imino-thiazolidine-4-one; 3-cyclohexyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-hydroxy-1-naphthyl)imino-thiazolidine-4-one; 4-ethylamino-3-[3-benzyl-5-(6-fluoro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(6-ethoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(6-nitro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(5-trifluoromethyl-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(6-methylcarbonylamino-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(5-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(6-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(5-ethylaminocarbonyloxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(5-methoxycarbonylmethoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(5-aminocarbonylmethoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(5-(2-hydroxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(4-methoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(4-methyl-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(4-chloro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(5-(2-chloroethylaminocarbonyloxy)-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(5-(2-methylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-propyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 3-(3-pyridylmethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(3-acetylphenyl)imino-thiazolidine-4-one; 3-(3-pyridylmethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one; 4-ethylamino-3-[3-(3-pyridylmethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-(2-furylmethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 3-(4-methoxycarbonylbenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one; 3-(4-hydroxycarbonylbenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one; 4-ethylamino-3-[3-(2-phenylethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-(2-(4-morpholinyl)-1-ethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 3-benzyl-5-(3-methylthiazolin-2-ylidene)-2-(4-methylcarbonylaminophenyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-4-phenylthiazol-2-ylidene)-2-(4-methylcarbonylaminophenyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-4-phenylthiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methylthiazol-2-ylidene)-2-(4-methylcarbonylaminophenyl)imino-thiazolidine-4-one; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-phenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4,5-dimethylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-phenyl-5-methylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4,5-butylenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-ethylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-nitrophenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-fluorophenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-chlorophenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-methylphenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-methoxyphenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-methyl-5-acetylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4,5-propylenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4,5-diphenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-methylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-(3-pyridylmethyl)-5-(3-methyl-4,5-butylenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; and 3-(4-methoxycarbonylbenzyl)-5-(3-methyl-4,5-butylenylthiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one.
 24. A compound selected from: 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-8-ylimino)thiazolidin-4-one; 3-benzyl-2-(8-hydroxyquinolin-5-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-butylaminobenzonitrile; 4-benzylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-cyclopentylaminobenzonitrile; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(pyrrolidin-1-ylamino)benzonitrile; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-pyrrolidin-1-ylbenzonitrile; 3-benzyl-2-(isoquinolin-5-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-benzyl-2-(isoquinolin-1-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; N-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}acetamide; 3-(4-acetylphenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzamide; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(naphthalen-1-ylimino)thiazolidin-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(naphthalen-2-ylimino)thiazolidin-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(pyridin-2-ylimino)thiazolidin-4-one; 4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzenesulfonamide; N-acetyl-4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzenesulfonamide; 2-(3-acetylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-3-pyridin-3-ylmethylthiazolidin-4-one; N-{5-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]pyridin-2-yl}acetamide; N-{5-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-2-cyanophenyl}acetamide; 2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-3-pyridin-3-ylmethylthiazolidin-4-one; 4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-pyridin-3-ylmethylthiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-furan-2-ylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 2-(5-acetyl-2-methylaminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; N-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2,2,2-trifluoroacetamide; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzoic acid methyl ester; 4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-phenethylthiazolidin-2-ylideneamino]benzonitrile; 2-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoic acid; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzoic acid tert-butyl ester; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzoic acid; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(2-hydroxyethylamino)benzonitrile; {2-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-cyanophenylamino}acetic acid methyl ester; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-N-ethyl-4-ethylaminobenzamide; {2-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-cyanophenylamino}acetic acid; 3-benzyl-2-(4-ethylaminopyridin-3-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; N-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-3-ethylaminophenyl}acetamide; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(2-dimethylaminoethylamino)benzonitrile; 4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-N-ethyl-3-ethylaminobenzamide; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-N-(2-dimethylaminoethyl)-4-ethylaminobenzamide; 3-benzyl-2-[5-(4,5-dihydrooxazol-2-yl)-2-ethylamino-phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-[3-benzyl-5-(1-methyl-1H-quinolin-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 2-(5-acetyl-2-ethylaminophenylimino)-3-benzyl-5-(1-methyl-1H-quinolin-2-ylidene)thiazolidin-4-one; 3-benzyl-2-benzylimino-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 2-(3-acetylphenylimino)-3-furan-2-ylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; N-{4-[3-furan-2-ylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}acetamide; [2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-yl]acetic acid methyl ester; N-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-2-cyanophenyl}acetamide; 2-(5-acetyl-2-ethoxyphenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 2-(5-acetyl-2-hydroxyphenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 2-(5-acetyl-2-ethylaminophenylimino)-3-benzyl-1-methyl-5-(3-methyl-3H-benzothiazol-2-ylidene)imidazolidin-4-one; 4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-3-(2-morpholin-4-ylethyl)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-(4-methoxybenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-(3-methoxybenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-(2-methoxybenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}succinamic acid; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}benzenesulfonamide; thiophene-2-sulfonic acid {3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}amide; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-3-methoxybenzamide; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}methanesulfonamide; {3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}carbamic acid ethyl ester; 3-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-1,1-dimethylurea; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-morpholin-4-ylacetamide; N-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-morpholin-4-ylacetamide; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-dimethylaminoacetamide; {4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}carbamic acid ethyl ester; N-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-dimethylaminoacetamide; N-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}methanesulfonamide; 4-ethylamino-3-[3-(3-hydroxybenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-(3-fluorobenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-(3-fluorobenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-(3-trifluoromethylbenzyl)thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-(2-trifluoromethylbenzyl)thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-3-(3-methylbenzyl)-4-oxothiazolidin-2-ylideneamino]benzonitrile; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-morpholin-4-ylacetamide; 3-[3-(3-chlorobenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 3-[3-(3-bromobenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2,2,2-trifluoroacetamide; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-dimethylaminoacetamide; 4-methylpiperazine-1-carboxylic acid {3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}amide; 2-(5-amino-2-ethylaminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-(4-methylpiperazin-1-yl)acetamide; N-{3-[3-benzyl-5-(5-methoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-dimethylaminoacetamide; N-{3-[3-benzyl-5-(5-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-dimethylaminoacetamide; N-(3-{3-benzyl-5-[5-(2-chloroethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylamino-phenyl)-2-dimethylaminoacetamide; N-(3-{3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylamino-phenyl)-2-dimethylaminoacetamide; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-methoxyacetamide; N-(3-{3-benzyl-5-[5-(2-dimethylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylaminoacetamide; N-(3-{3-benzyl-5-[5-(2-hydroxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylaminoacetamide; 2-(5-acetyl-2-ethylaminophenylimino)-5-[5-(2-chloroethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-furan-2-ylmethylthiazolidin-4-one; 2-(5-acetyl-2-ethylaminophenylimino)-3-furan-2-ylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; N-(3-{3-benzyl-5-[5-(2-chloroethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-methoxyacetamide; N-{4-ethylamino-3-[3-furan-2-ylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-methoxyacetamide; N-(3-{3-benzyl-5-[5-(2-dimethylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-methoxyacetamide; 2-(5-acetyl-2-ethylaminophenylimino)-5-[5-(2-dimethylamino-ethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-furan-2-ylmethylthiazolidin-4-one; N-(3-{5-[5-(2-dimethylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-furan-2-ylmethyl-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-methoxyacetamide; acetic acid {3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenylcarbamoyl}methyl ester; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-hydroxyacetamide; N-(3-{3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-hydroxyacetamide; 2-(3-acetylphenylimino)-3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]thiazolidin-4-one; 2-(5-acetyl-2-ethylaminophenylimino)-3-furan-2-ylmethyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]thiazolidin-4-one; N-(4-ethylamino-3-{3-furan-2-ylmethyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}phenyl)-2-methoxyacetamide; 2-(5-acetyl-2-ethylaminophenylimino)-3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]thiazolidin-4-one; N-(3-{3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-methoxyacetamide; N-(3-{5-[5-(2-aminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-benzyl-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylaminoacetamide; 2-dimethylamino-N-{3-[3-furan-2-ylmethyl-5-(5-methoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-phenyl}acetamide; 3-(3′-benzyl-3,4,5-trimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3-[3-benzyl-5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 3-(3′-benzyl-4-ethyl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3-[3′-benzyl-3-methyl-4-(4-nitrophenyl)-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(4-fluorophenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(4-chloro-phenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-(3′-benzyl-3-methyl-4′-oxo-4-p-tolyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(4-methoxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-(5-acetyl-3′-benzyl-3,4-dimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3-[3-benzyl-5-(3-methyl-3,4,5,6-tetrahydrocyclopentathiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 3-(3′-benzyl-3-methyl-4′-oxo-4,5-diphenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3-(3′-benzyl-3,4-dimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 4-ethylamino-3-[5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)-4-oxo-3-pyridin-3-ylmethylthiazolidin-2-ylideneamino]benzonitrile; methyl 4-[2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoate; methyl 4-[2-(5-acetyl-2-ethylamino-phenylimino)-5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoate; 4-[2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoic acid; 3-[3-benzyl-5-(1-methyl-4,5,6,7-tetrahydro-1H-thiazolo[5,4-c]pyridin-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; methyl 3-[2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoate; 3-[2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoic acid; 2-(5-acetyl-2-ethylaminophenylimino)-3-benzyl-5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-(3′-benzyl-4-biphenyl-4-yl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3-(3′-benzyl-3-methyl-4-naphthalen-2-yl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(4-bromophenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-3-methyl-4-(2-nitrophenyl)-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)-3-pyridin-3-ylmethylthiazolidin-4-one; 3-[3′-benzyl-4-(2-methoxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(3-fluorophenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-3-methyl-4′-oxo-4-(4-trifluoromethylphenyl)-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-3-methyl-4′-oxo-4-(4-trifluoromethoxyphenyl)-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(2,4-dimethoxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-(3′-benzyl-5-ethyl-3-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3-[3′-benzyl-3-methyl-4′-oxo-4-(2-trifluoromethylphenyl)-3′,4′-dihydro-3H-2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(3-bromophenyl)-3,5-dimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(3-methoxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-benzyl-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxyisopropyl)-phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-(3′-benzyl-4-chloromethyl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3′-benzyl-2′-(5-cyano-2-ethylaminophenylimino)-3-methyl-4′-oxo-3′,4′-dihydro-3H,2′H-[2,5′]bithiazolylidene-4-carboxylic acid ethyl ester; 3-(4,3′-dibenzyl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3′-benzyl-2′-(5-cyano-2-ethylaminophenylimino)-3-methyl-4′-oxo-3′,4′-dihydro-3H,2′H-[2,5′]bithiazolylidene-4-carboxylic acid; 3-benzyl-2-[2-ethylamino-5-(1-hydroxyethyl)phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-[3′-benzyl-4-(2-hydroxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-benzyl-2-[2-ethylamino-5-(1-hydroxyiminoethyl)phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-benzyl-2-[2-ethylamino-5-(1-methoxyiminoethyl)phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-benzyl-2-[5-(1-benzyloxyiminoethyl)-2-ethylaminophenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-benzyl-2-{2-ethylamino-5-[1-(phenylhydrazono)ethyl]-phenylimino}-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-(4,3′-dibenzyl-3,5-dimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3-[3-cyclohexylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(3-hydroxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(4-hydroxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-(3′-benzyl-3,4-dimethyl-4′-oxo-5-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-3,5-dimethyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; 2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-3,4-dimethyl-5-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; 2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-4-(4-methoxyphenyl)-3,5-dimethyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; 2′-(5-acetyl-2-ethylaminophenylimino)-4,3′-dibenzyl-3-methyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; 2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-4-(2-methoxyphenyl)-3,5-dimethyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; 3-{3-benzyl-5-[5-(2-dimethylaminoacetyl)-1-methyl-4,5,6,7-tetrahydro-1H-thiazolo[5,4-c]pyridin-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-4-(3-methoxyphenyl)-3,5-dimethyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; 2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-4-(3-hydroxyphenyl)-3,5-dimethyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; 2′-(5-acetyl-2-ethylaminophenylimino)-3,3′-dibenzyl-5-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; N-(3-{3-benzyl-5-[5-(2-acetoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylaminoacetamide; 2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-3-(2-methoxyethyl)-5-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; 2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-3-(3-methoxypropyl)-5-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; [2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-5-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-2′H-[2,5′]bithiazolyliden-3-yl]acetic acid methyl ester; [2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-5-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-2′H-[2,5′]bithiazolyliden-3-yl]acetic acid; 2-[2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-5-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-2′H-[2,5′]bithiazolyliden-3-yl]ethyl acetate; 2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-3-(2-hydroxyethyl)-5-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; N-[3-(3′-benzyl-3,5-dimethyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminophenyl]-2-methoxyacetamide; N-[3-(3′-benzyl-3,5-dimethyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminophenyl]-2-dimethylaminoacetamide; 3-[3-cyclohexyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 3-[3-allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 3-allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-5-ylimino)thiazolidin-4-one; 3-allyl-2-(4-hydroxy-5-isopropyl-2-methylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-phenylthiazolidin-2-ylideneamino]benzonitrile; 3-cyclohexyl-2-(2-hydroxynaphthalen-1-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-allyl-2-(2-hydroxynaphthalen-1-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 2-(4-cyclohexylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-3-phenylthiazolidin-4-one; 3-[3-benzyl-5-(6-fluoro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 3-[3-benzyl-5-(5-chloro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 3-[3-benzyl-5-(6-ethoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-propylthiazolidin-2-ylideneamino]benzonitrile; 3-[3-benzyl-5-(3-methyl-6-nitro-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; N-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}acetamide; 3-[3-benzyl-5-(6-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; ethylcarbamic acid 2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yl ester; {2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yloxy}acetic acid methyl ester; 2-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yloxy}acetamide; (2-chloroethyl)carbamic acid 2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yl ester; 3-{3-benzyl-5-[3-methyl-5-(2-methylaminoethoxy)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[5-(3-hydroxypropoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; (3-chloropropyl)carbamic acid 2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yl ester; 3-(3-benzyl-5-{3-methyl-5-[2-(4-methylpiperazin-1-yl)-ethoxy]-3H-benzothiazol-2-ylidene}-4-oxothiazolidin-2-ylideneamino)-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[3-methyl-5-(2-piperidin-4-ylethoxy)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[5-(2-dimethylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; {2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yloxy}acetic acid; 3-{3-benzyl-5-[6-(2-hydroxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[6-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[3-methyl-6-(2-morpholin-4-ylethoxy)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[3-methyl-4-methoxy-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[3-methyl-4-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[3-methyl-4-chloro-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[3-methyl-6-trifluoromethoxy-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-[3-benzyl-5-(3,5,6-trimethyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 3-[3-benzyl-5-(3-methyl-5-acetamido-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; N-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-6-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yl}-2,2,2-trifluoroacetamide; 3-[5-(6-amino-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; N-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-N′,N″-di(tert-butoxycarbonyl)guanidine; 2-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-1,1,-dimethylurea; N-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yl}-2,2,2-trifluoroacetamide; 3-[5-(5-amino-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; {2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}carbamic acid ethyl ester; N-[2-(3-benzyl-2-{5-cyano-2-[ethyl-(2-morpholin-ylethyl)amino]phenylimino}-4-oxothiazilidin-5-ylidene)-3-methyl-2,3-dihydrobenzothiazol-6-yl]-2,2,2-trifluoroacetamide; N-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-2,2,2-trifluoro-N-(2-morpholin-4ylethyl)acetamide; 3-{3-benzyl-5-[3-methyl-6-(2-morpholin-4-yl-ethylamino)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[3-methyl-6-(2-piperidin-1-yl-ethylamino)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; N-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yl}-2,2,2-trifluoro-N-(2-morpholin-4ylethyl)acetamide; 3-{3-benzyl-5-[3-methyl-5-(2-morpholin-4-yl-ethylamino)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; N-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}guanidine; 3-{3-benzyl-5-[3-methyl-6-(4-trifluoromethylbenzylamino)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; N-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-N-(3-fluoropropyl)-2,2,2-trifluoroacetamide; N-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-N-(3-cyanopropyl)-2,2,2-trifluoroacetamide; 3-{3-benzyl-5-[6-(3-cyanopropylamino)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-(ethylamino)benzonitrile; 3-{3-benzyl-5-[6-(3-hydroxypropylamino)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-(ethylamino)benzonitrile; and 3-{3-benzyl-5-[6-(2-methoxyethylamino)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-(ethylamino)benzonitrile.
 25. A pharmaceutical composition, comprising, in a pharmaceutically acceptable carrier, a compound formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, E and G are selected from (i) or (ii) as follows: (i) A and G are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium, substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³, or A and G together form substituted or unsubstituted alkylene, substituted or unsubstituted azaalkylene, substituted or unsubstituted oxaalkylene, substituted or unsubstituted thiaalkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted 1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene, or substituted or unsubstituted 2-aza-1,3-butadienylene;  D and E are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, halo and pseudohalo or D and E together form a bond; or (ii) A and D; or E and G; together form substituted or unsubstituted alkylene, substituted or unsubstituted azaalkylene, substituted or unsubstituted oxaalkylene, or substituted or unsubstituted thiaalkylene; and the others of A, D, E and G are selected as in (i); X¹ and X² are each independently selected from O, S, S(═O), S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ and R² are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium, substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; R³ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylium, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ and C(═J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted, heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl or C(═J)R¹³; J is O, S or NR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ and R¹⁶ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl and heteroaryliumalkyl moieties of A, D, E, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one or more substituents each independently selected from Q¹, where Q¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino, hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo, arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy where y is 1 or 2; or two Q¹ groups, which substitute the same atom, together form alkylene; and each Q¹ is independently unsubstituted or substituted with one or more substituents each independently selected from Q²; each Q² is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy where y is 1 or 2; or two Q² groups, which substitute the same atom, together form alkylene; each Q² is independently unsubstituted or substituted with one or more substituents each independently selected from alkyl, halo and pseudohalo; R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹ together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹.
 26. The pharmaceutical composition of claim 25, wherein the compound has formulae II:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, E and G are selected from (i) or (ii) as follows: (i) A and G are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium, substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³, or A and G together form substituted or unsubstituted alkylene, substituted or unsubstituted azaalkylene, substituted or unsubstituted oxaalkylene, substituted or unsubstituted thiaalkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted 1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene, or substituted or unsubstituted 2-aza-1,3-butadienylene;  D and E are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, halo and pseudohalo or D and E together form a bond; or (ii) A and D; or E and G; together form substituted or unsubstituted alkylene, substituted or unsubstituted azaalkylene, substituted or unsubstituted oxaalkylene, or substituted or unsubstituted thiaalkylene; and the others of A, D, E and G are selected as in (i); X¹ is selected from O, S, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; R¹ and R² are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium, substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; R³ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylium, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; where: R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ and C(═J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl or C(═J)R¹³; J is O, S or NR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ and R¹⁶ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl and heteroaryliumalkyl moieties of R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one or more substituents each independently selected from Q¹, where Q¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups, which substitute the same atom, together form alkylene; each Q¹ is independently unsubstituted or substituted with one or more substituents each independently selected from Q²; each Q² is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy (i.e., —O—(CH₂)_(y)—O—), thioalkylenoxy (i.e., —S—(CH₂)_(y)—O—)or alkylenedithioxy (i.e., —S—(CH₂)_(y)—S—) where y is 1 or 2; or two Q² groups, which substitute the same atom, together form alkylene; R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹ together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹.
 27. The pharmaceutical composition of claim 25, wherein A and G are each independently selected from hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted aryl, or together form substituted or unsubstituted 1,3-butadienyl.
 28. The pharmaceutical composition of claim 25, wherein A and G are each independently hydrogen, methyl or phenyl, or together form substituted or unsubstituted 1,3-butadienyl.
 29. The pharmaceutical composition of claim 25, wherein A and G are both hydrogen.
 30. The pharmaceutical composition of claim 25, wherein D and E are each hydrogen, or together form a bond.
 31. The pharmaceutical composition of claim 25, wherein D and E together form a bond, and A and G together form substituted or unsubstituted 1,3-butadienyl.
 32. The pharmaceutical composition of claim 25, wherein the compound has formulae III:

or a pharmaceutically acceptable derivative thereof, wherein: each R⁴ is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted guanidino, substituted or unsubstituted isothioureido, halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² or C(═J)R¹³; x is an integer from 0 to 4; and the amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl and heteroaryliumalkyl moieties of R⁴ are unsubstituted or substituted with one or more substituents each independently selected from Q².
 33. The pharmaceutical composition of claim 32, wherein the compound has formulae IV:

or a pharmaceutically acceptable derivative thereof, wherein: each R⁴ is independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted guanidino, substituted or unsubstituted isothioureido, halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² or C(═J)R¹³; x is an integer from 0 to 4; and the amino, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl and heteroaryliumalkyl moieties of R⁴ are unsubstituted or substituted with one or more substituents each independently selected from Q².
 34. The pharmaceutical composition of claim 25, wherein X¹ is O, S or NR⁵.
 35. The pharmaceutical composition of claim 25, wherein X¹ is O or S.
 36. The pharmaceutical composition of claim 25, wherein X¹ is S.
 37. The pharmaceutical composition of claim 25, wherein R¹ is substituted or unsubstituted alkyl.
 38. The pharmaceutical composition of claim 25, wherein R¹ is methyl.
 39. The pharmaceutical composition of claim 25, wherein R² is substituted or unsubstituted alkyl or substituted or unsubstituted aralkyl.
 40. The pharmaceutical composition of claim 25, wherein R² is ethyl, n-butyl or benzyl.
 41. The pharmaceutical composition of claim 25, wherein R² is benzyl.
 42. The pharmaceutical composition of claim 25, wherein R³ is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.
 43. The pharmaceutical composition of claim 25, wherein R³ is substituted or unsubstituted phenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted pyridyl, substituted or unsubstituted indazolyl, or substituted or unsubstituted quinolinyl.
 44. The pharmaceutical composition of claim 25, wherein R³ is substituted or unsubstituted phenyl.
 45. The pharmaceutical composition of claim 25, wherein Q¹ is selected from halo, hydroxy, nitrile, nitro, hydroxycarbonyl, alkyl, haloalkyl, polyhaloalkyl, heteroaryl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkoxy, perfluoroalkoxy, aralkoxy, amino, alkylamino, dialkylamino, haloalkylamino, alkylcarbonylamino, dialkylcarbonyloxy or heterocyclyl; or two Q¹ groups, which substitute atoms in a 1,2 arrangement, form alkylenedioxy.
 46. The pharmaceutical composition of claim 25, wherein Q¹ is methoxy, dimethylamino, NH₂, benzyloxy, hydroxy, CN, isopropyl, methyl, nitro, ethylamino, trifluoromethyl, acetyl, chloro, n-propyl, ethoxy, methylcarbonylamino, CONH₂, methoxycarbonyl, methylamino, trifluoromethoxy, imidazolyl, hydroxycarbonyl, isopropylamino, tert-butylamino, 2,2,2-trifluoroethylamino, piperidinyl, dimethylaminocarbonyloxy, 2-hydroxyethoxy, 2-(N-morpholinyl)ethoxy or morpholinyl, or two Q¹ groups, which substitute atoms in a 1,2 arrangement, form methylenedioxy.
 47. The pharmaceutical composition of claim 25, wherein the compound has formulae V:

or a pharmaceutically acceptable derivative thereof, wherein: R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently selected from hydrogen, halo, pseudohalo, hydroxyl, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl, or any two of R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹, which substitute adjacent carbons on the ring, together form alkylenedioxy; and the aryl and heteroaryl groups of R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are unsubstituted or substituted with one or more substituents each independently selected from R³⁰, where R³⁰ is alkyl, halo, pseudohalo, alkoxy, aryloxy or alkylenedioxy.
 48. The pharmaceutical composition of claim 25, wherein the compound has formulae VI:

or a pharmaceutically acceptable derivative thereof, where R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently selected from hydrogen, halo, pseudohalo, hydroxyl, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl, or any two of R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹, which substitute adjacent carbons on the ring, together form alkylenedioxy; and the aryl and heteroaryl groups of R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are unsubstituted or substituted with one or more substituents each independently selected from R³⁰, where R³⁰ is alkyl, halo, pseudohalo, alkoxy, aryloxy or alkylenedioxy.
 49. The pharmaceutical composition of claim 25, wherein the compound has formulae VII:

or a pharmaceutically acceptable derivative thereof, where R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently selected from hydrogen, halo, pseudohalo, hydroxyl, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl, or any two of R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹, which substitute adjacent carbons on the ring, together form alkylenedioxy; and the aryl and heteroaryl groups of R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are unsubstituted or substituted with one or more substituents each independently selected from R³⁰, where R³⁰ is alkyl, halo, pseudohalo, alkoxy, aryloxy or alkylenedioxy.
 50. The pharmaceutical composition of claim 25, wherein the compound has formulae VIII:

or a pharmaceutically acceptable derivative thereof, where R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently selected from hydrogen, halo, pseudohalo, hydroxyl, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl, or any two of R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹, which substitute adjacent carbons on the ring, together form alkylenedioxy; and the aryl and heteroaryl groups of R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are unsubstituted or substituted with one or more substituents each independently selected from R³⁰, where R³⁰ is alkyl, halo, pseudohalo, alkoxy, aryloxy or alkylenedioxy.
 51. The pharmaceutical composition of claim 25, wherein the compound has formulae IX:

or a pharmaceutically acceptable derivative thereof, where R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently selected from hydrogen, halo, pseudohalo, hydroxyl, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl, or any two of R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹, which substitute adjacent carbons on the ring, together form alkylenedioxy; and the aryl and heteroaryl groups of R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are unsubstituted or substituted with one or more substituents each independently selected from R³⁰, where R³⁰ is alkyl, halo, pseudohalo, alkoxy, aryloxy or alkylenedioxy.
 52. The pharmaceutical composition of claim 48, wherein R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently selected from hydrogen, halo, hydroxy, nitrile, nitro, hydroxycarbonyl, alkyl, haloalkyl, polyhaloalkyl, heteroaryl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkoxy, perfluoroalkoxy, aralkoxy, amino, alkylamino, dialkylamino, haloalkylamino, alkylcarbonylamino or heterocyclyl; or any two of R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹, which substitute adjacent carbons on the ring, form alkylenedioxy.
 53. The pharmaceutical composition of claim 48, wherein R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹ are each independently hydrogen, methoxy, dimethylamino, NH₂, benzyloxy, hydroxy, CN, isopropyl, methyl, nitro, ethylamino, trifluoromethyl, acetyl, chloro, n-propyl, ethoxy, methylcarbonylamino, CONH₂, methoxycarbonyl, methylamino, trifluoromethoxy, imidazolyl, hydroxycarbonyl, isopropylamino, tert-butylamino, 2,2,2-trifluoroethylamino, piperidinyl or morpholinyl, or any two of R¹⁷, R¹⁸, R¹⁹, R²⁰ and R²¹, which substitute adjacent carbons on the ring, form methylenedioxy.
 54. The pharmaceutical composition of claim 25, wherein the compound is selected from: 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-phenylimino-thiazolidine-4-one; 3-benzyl-2-(4-methoxyphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-benzyl-2-(4-dimethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 2-(4-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-6-ylimino)-thiazolidine-4-one; 2-(2-aminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-benzyl-2-(4-benzyloxyphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-benzyl-2-(2-hydroxy-1-naphthylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 3-benzyl-2-(4-hydroxy-5-isopropyl-2-methylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-benzyl-2-(2-ethylamino-5-nitrophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-[3-(trifluoromethyl)phenylimino]thiazolidine-4-one; 2-(3-acetylphenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-benzyl-2-(3-chlorophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-propylphenylimino)thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-5-ylimino)thiazolidine-4-one; 3-benzyl-2-(2-ethoxyphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}acetamide; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzamide; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoic acid, methyl ester; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(pyridin-3-ylimino)-thiazolidine-4-one; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethoxyphenyl}acetamide; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(pyridin-4-ylimino)thiazolidine-4-one; 4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoic acid, methyl ester; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-[4-(trifluoromethoxy)phenylimino]thiazolidine-4-one; 3-benzyl-2-(1H-indazol-5-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-benzyl-2-(4-imidazol-1-ylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 2-(benzo[1,3]dioxol-5-ylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoic acid; 3-benzyl-2-[2-(ethylamino)phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidine-4-one; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(methylamino)benzonitrile; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(ethylamino)benzonitrile; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidin-2-ylideneamino]-4-(isopropylamino)benzonitrile; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(dimethylamino)benzonitrile; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(tert-butylamino)benzonitrile; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(2,2,2-trifluoroethylamino)benzonitrile; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-piperidin-1-ylbenzonitrile; 2-[5-acetyl-2-(ethylamino)phenylimino]-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-6-ylimino)thiazolidin-4-one; 3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-morpholin-4-yl-phenylimino)thiazolidin-4-one; 3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(methylamino)benzonitrile; 4-dimethylamino-3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 3-[3-ethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(isopropylamino)benzonitrile; 3-[3-butyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 3-benzyl-5-(3-methyl-3H-benzoxazol-2-ylidene)-2-(quinolin-5-ylimino)thiazolidin-4-one; N-[4-(3′-benzyl-3-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]-bithiazolyliden-2′-ylideneamino)phenyl]acetamide; 2′-[5-acetyl-2-(ethylamino)phenylimino]-3′-benzyl-3-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; 3-(3′-benzyl-3-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazol-yliden-2′-ylideneamino)-4-(ethylamino)benzonitrile; N-[4-(3′-benzyl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)phenyl]acetamide; N-[4-(3′-benzyl-3-methyl-4′-oxo-[2,5′]bithiazolidinyliden-2′-ylideneamino)phenyl]acetamide; 3-(3′-benzyl-3,5-dimethyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]-bithiazolyliden-2′-ylideneamino)-4-(ethylamino)benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-5-chloro-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 3-phenyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-cyclohexylphenyl)imino-thiazolidine-4-one; 3-allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-hydroxy-1-naphthyl)imino-thiazolidine-4-one; 4-ethylamino-3-[3-phenyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-5-methoxy-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 3-allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(5-quinolyl)imino-thiazolidine-4-one; 4-ethylamino-3-[3-allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 3-phenyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-benzylamino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(8-quinolyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(8-hydroxy-5-quinolyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(5-isoquinolyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(1-isoquinolyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-methylcarbonylamino)phenylimino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-methylcarbonyl)phenylimino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-aminocarbonyl)phenylimino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(1-naphthyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-naphthyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-pyridyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-aminosulfonyl)phenylimino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-methylcarbonylaminosulfonyl)phenylimino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(3-methylcarbonyl)phenylimino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-methylcarbonylamino-5-pyridyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-cyano-5-methylcarbonylaminophenyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-methylcarbonylphenyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-methylamino-5-methylcarbonylphenyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-trifluoromethylcarbonylaminophenyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-methoxycarbonylphenyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-hydroxycarbonylphenyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-tert-butoxycarbonylphenyl)imino-thiazolidine-4-one; 4-butylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-benzylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-cyclopentylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-pyrrolidinylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-pyrrolidinyl-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-cyclohexyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 3-allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(4-hydroxy-2-methyl-5-isopropylphenyl)imino-thiazolidine-4-one; 3-cyclohexyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-hydroxy-1-naphthyl)imino-thiazolidine-4-one; 4-ethylamino-3-[3-benzyl-5-(6-fluoro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(6-ethoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(6-nitro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(5-trifluoromethyl-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(6-methylcarbonylamino-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(5-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(6-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(5-ethylaminocarbonyloxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(5-methoxycarbonylmethoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(5-aminocarbonylmethoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(5-(2-hydroxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(4-methoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(4-methyl-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(4-chloro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(5-(2-chloroethylaminocarbonyloxy)-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(5-(2-methylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-propyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 3-(3-pyridylmethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(3-acetylphenyl)imino-thiazolidine-4-one; 3-(3-pyridylmethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one; 4-ethylamino-3-[3-(3-pyridylmethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-(2-furylmethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 3-(4-methoxycarbonylbenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one; 3-(4-hydroxycarbonylbenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one; 4-ethylamino-3-[3-(2-phenylethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-(2-(4-morpholinyl)-1-ethyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 3-benzyl-5-(3-methylthiazolin-2-ylidene)-2-(4-methylcarbonylaminophenyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-4-phenylthiazol-2-ylidene)-2-(4-methylcarbonylaminophenyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methyl-4-phenylthiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one; 3-benzyl-5-(3-methylthiazol-2-ylidene)-2-(4-methylcarbonylaminophenyl)imino-thiazolidine-4-one; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-phenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4,5-dimethylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-phenyl-5-methylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4,5-butylenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-ethylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-nitrophenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-fluorophenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-chlorophenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-methylphenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-(4-methoxyphenyl)thiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-methyl-5-acetylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4,5-propylenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4,5-diphenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-benzyl-5-(3-methyl-4-methylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-(3-pyridylmethyl)-5-(3-methyl-4,5-butylenylthiazol-2-ylidene)-4-oxo-thiazolidin-2-ylideneamino]benzonitrile; and 3-(4-methoxycarbonylbenzyl)-5-(3-methyl-4,5-butylenyllthiazol-2-ylidene)-2-(2-ethylamino-5-acetylphenyl)imino-thiazolidine-4-one.
 55. The pharmaceutical composition of claim 25, wherein the compound is selected from: 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-8-ylimino)thiazolidin-4-one; 3-benzyl-2-(8-hydroxyquinolin-5-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-butylaminobenzonitrile; 4-benzylamino-3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-cyclopentylaminobenzonitrile; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(pyrrolidin-1-ylamino)benzonitrile; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-pyrrolidin-1-ylbenzonitrile; 3-benzyl-2-(isoquinolin-5-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-benzyl-2-(isoquinolin-1-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; N-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}acetamide; 2-(4-acetylphenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzamide; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(naphthalen-1-ylimino)thiazolidin-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(naphthalen-2-ylimino)thiazolidin-4-one; 3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(pyridin-2-ylimino)thiazolidin-4-one; 4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzenesulfonamide; N-acetyl-4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzenesulfonamide; 2-(3-acetylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-3-pyridin-3-ylmethylthiazolidin-4-one; N-{5-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]pyridin-2-yl}acetamide; N-{5-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-2-cyanophenyl}acetamide; 2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-3-pyridin-3-ylmethylthiazolidin-4-one; 4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-pyridin-3-ylmethylthiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-furan-2-ylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 2-(5-acetyl-2-methylaminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; N-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2,2,2-trifluoroacetamide; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzoic acid methyl ester; 4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-phenethylthiazolidin-2-ylideneamino]benzonitrile; 2-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzoic acid; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzoic acid tert-butyl ester; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzoic acid; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(2-hydroxyethylamino)benzonitrile; {2-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-cyanophenylamino}acetic acid methyl ester; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-N-ethyl-4-ethylaminobenzamide; {2-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-cyanophenylamino}acetic acid; 3-benzyl-2-(4-ethylaminopyridin-3-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; N-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-3-ethylaminophenyl}acetamide; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-(2-dimethylaminoethylamino)benzonitrile; 4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-N-ethyl-3-ethylaminobenzamide; 3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-N-(2-dimethylaminoethyl)-4-ethylaminobenzamide; 3-benzyl-2-[5-(4,5-dihydrooxazol-2-yl)-2-ethylamino-phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-[3-benzyl-5-(1-methyl-1H-quinolin-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 2-(5-acetyl-2-ethylaminophenylimino)-3-benzyl-5-(1-methyl-1H-quinolin-2-ylidene)thiazolidin-4-one; 3-benzyl-2-benzylimino-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 2-(3-acetylphenylimino)-3-furan-2-ylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; N-{4-[3-furan-2-ylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}acetamide; [2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-yl]acetic acid methyl ester; N-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-2-cyanophenyl}acetamide; 2-(5-acetyl-2-ethoxyphenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 2-(5-acetyl-2-hydroxyphenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 2-(5-acetyl-2-ethylaminophenylimino)-3-benzyl-1-methyl-5-(3-methyl-3H-benzothiazol-2-ylidene)imidazolidin-4-one; 4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-3-(2-morpholin-4-ylethyl)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-(4-methoxybenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-(3-methoxybenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-(2-methoxybenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}succinamic acid; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}benzenesulfonamide; thiophene-2-sulfonic acid {3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}amide; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-3-methoxybenzamide; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}methanesulfonamide; {3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}carbamic acid ethyl ester; 3-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-1,1-dimethylurea; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-morpholin-4-ylacetamide; N-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-morpholin-4-ylacetamide; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-dimethylaminoacetamide; {4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}carbamic acid ethyl ester; N-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-dimethylaminoacetamide; N-{4-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}methanesulfonamide; 4-ethylamino-3-[3-(3-hydroxybenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-(3-fluorobenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[3-(3-fluorobenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-(3-trifluoromethylbenzyl)thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-(2-trifluoromethylbenzyl)thiazolidin-2-ylideneamino]benzonitrile; 4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-3-(3-methylbenzyl)-4-oxothiazolidin-2-ylideneamino]benzonitrile; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-morpholin-4-ylacetamide; 3-[3-(3-chlorobenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 3-[3-(3-bromobenzyl)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2,2,2-trifluoroacetamide; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-dimethylaminoacetamide; 4-methylpiperazine-1-carboxylic acid {3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}amide; 2-(5-amino-2-ethylaminophenylimino)-3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-(4-methylpiperazin-1-yl)acetamide; N-{3-[3-benzyl-5-(5-methoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-dimethylaminoacetamide; N-{3-[3-benzyl-5-(5-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-dimethylaminoacetamide; N-(3-{3-benzyl-5-[5-(2-chloroethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylamino-phenyl)-2-dimethylaminoacetamide; N-(3-{3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylamino-phenyl)-2-dimethylaminoacetamide; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-methoxyacetamide; N-(3-{3-benzyl-5-[5-(2-dimethylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylaminoacetamide; N-(3-{3-benzyl-5-[5-(2-hydroxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylaminoacetamide; 2-(5-acetyl-2-ethylaminophenylimino)-5-[5-(2-chloroethoxy)-3-methyl-3H-enzothiazol-2-ylidene]-3-furan-2-ylmethylthiazolidin-4-one; 2-(5-acetyl-2-ethylaminophenylimino)-3-furan-2-ylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; N-(3-{3-benzyl-5-[5-(2-chloroethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-methoxyacetamide; N-{4-ethylamino-3-[3-furan-2-ylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]phenyl}-2-methoxyacetamide; N-(3-{3-benzyl-5-[5-(2-dimethylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-methoxyacetamide; 2-(5-acetyl-2-ethylaminophenylimino)-5-[5-(2-dimethylamino-ethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-furan-2-ylmethylthiazolidin-4-one; N-(3-{5-[5-(2-dimethylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-furan-2-ylmethyl-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-methoxyacetamide; acetic acid {3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenylcarbamoyl}methyl ester; N-{3-[3-benzyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminophenyl}-2-hydroxyacetamide; N-(3-{3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazo(-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-hydroxyacetamide; 2-(3-acetylphenylimino)-3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]thiazolidin-4-one; 2-(5-acetyl-2-ethylaminophenylimino)-3-furan-2-ylmethyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]thiazolidin-4-one; N-(4-ethylamino-3-{3-furan-2-ylmethyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}phenyl)-2-methoxyacetamide; 2-(5-acetyl-2-ethylaminophenylimino)-3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]thiazolidin-4-one; N-(3-{3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-methoxyacetamide; N-(3-{5-[5-(2-aminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-3-benzyl-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylaminoacetamide; 2-dimethylamino-N-{3-[3-furan-2-ylmethyl-5-(5-methoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-phenyl}acetamide; 3-(3′-benzyl-3,4,5-trimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3-[3-benzyl-5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 3-(3′-benzyl-4-ethyl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3-[3′-benzyl-3-methyl-4-(4-nitrophenyl)-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(4-fluorophenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(4-chloro-phenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-(3′-benzyl-3-methyl-4′-oxo-4-p-tolyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(4-methoxyphenyl)3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-(5-acetyl-3′-benzyl-3,4-dimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3-[3-benzyl-5-(3-methyl-3,4,5,6-tetrahydrocyclopentathiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 3-(3′-benzyl-3-methyl-4′-oxo-4,5-diphenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3-(3′-benzyl-3,4-dimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 4-ethylamino-3-[5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)-4-oxo-3-pyridin-3-ylmethylthiazolidin-2-ylideneamino]benzonitrile; methyl 4-[2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoate; methyl 4-[2-(5-acetyl-2-ethylamino-phenylimino)-5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoate; 4-[2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoic acid; 3-[3-benzyl-5-(1-methyl-4,5,6,7-tetrahydro-1H-thiazolo[5,4-c]pyridin-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; methyl 3-[2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoate; 3-[2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-3-ylmethyl]benzoic acid; 2-(5-acetyl-2-ethylaminophenylimino)-3-benzyl-5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-(3′-benzyl-4-biphenyl4-yl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3-(3′-benzyl-3-methyl-4-naphthalen-2-yl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(4-bromophenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-3-methyl-4-(2-nitrophenyl)-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 2-(5-acetyl-2-ethylaminophenylimino)-5-(3-methyl-4,5,6,7-tetrahydro-3H-benzothiazol-2-ylidene)-3-pyridin-3-ylmethylthiazolidin-4-one; 3-[3′-benzyl-4-(2-methoxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(3-fluorophenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-3-methyl-4′-oxo-4-(4-trifluoromethylphenyl)-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-3-methyl-4′-oxo-4-(4-trifluoromethoxyphenyl)-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(2,4-dimethoxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-(3′-benzyl-5-ethyl-3-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3-[3′-benzyl-3-methyl-4′-oxo-4-(2-trifluoromethylphenyl)-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(3-bromophenyl)-3,5-dimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(3-methoxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-benzyl-2-[4-(1,1,1,3,3,3-hexafluoro-2-hydroxyisopropyl)-phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-(3′-benzyl-4-chloromethyl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3′-benzyl-2′-(5-cyano-2-ethylaminophenylimino)-3-methyl-4′-oxo-3′,4′-dihydro-3H,2′H-[2,5′]bithiazolylidene-4-carboxylic acid ethyl ester; 3-(4,3′-dibenzyl-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3′-benzyl-2′-(5-cyano-2-ethylaminophenylimino)-3-methyl-4′-oxo-3′,4′-dihydro-3H,2′H-[2,5′]bithiazolylidene-4-carboxylic acid; 3-benzyl-2-[2-ethylamino-5-(1-hydroxyethyl)phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-[3′-benzyl-4-(2-hydroxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-benzyl-2-[2-ethylamino-5-(1-hydroxyiminoethyl)phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-benzyl-2-[2-ethylamino-5-(1-methoxyiminoethyl)phenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-benzyl-2-[5-(1-benzyloxyiminoethyl)-2-ethylaminophenylimino]-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-benzyl-2-{2-ethylamino-5-[1-(phenylhydrazono)ethyl]-phenylimino}-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-(4,3′-dibenzyl-3,5-dimethyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 3-[3-cyclohexylmethyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(3-hydroxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-[3′-benzyl-4-(4-hydroxyphenyl)-3-methyl-4′-oxo-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino]-4-ethylaminobenzonitrile; 3-(3′-benzyl-3,4-dimethyl-4′-oxo-5-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminobenzonitrile; 2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-3,5-dimethyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; 2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-3,4-dimethyl-5-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; 2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-4-(4-methoxyphenyl)-3,5-dimethyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; 2′-(5-acetyl-2-ethylaminophenylimino)-4,3′-dibenzyl-3-methyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; 2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-4-(2-methoxyphenyl)-3,5-dimethyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; 3-{3-benzyl-5-[5-(2-dimethylaminoacetyl)-1-methyl-4,5,6,7-tetrahydro-1H-thiazolo[5,4-c]pyridin-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-4-(3-methoxyphenyl)-3,5-dimethyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; 2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-4-(3-hydroxyphenyl)-3,5-dimethyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; 2′-(5-acetyl-2-ethylaminophenylimino)-3,3′-dibenzyl-5-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; N-(3-{3-benzyl-5-[5-(2-acetoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminophenyl)-2-dimethylaminoacetamide; 2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-3-(2-methoxyethyl)-5-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; 2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-3-(3-methoxypropyl)-5-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; [2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-5-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-2′H-[2,5′]bithiazolyliden-3-yl]acetic acid methyl ester; [2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-5-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-2′H-[2,5′]bithiazolyliden-3-yl]acetic acid; 2-[2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-5-methyl-4′-oxo-4-phenyl-3′,4′-dihydro-2′H-[2,5′]bithiazolyliden-3-yl]ethyl acetate; 2′-(5-acetyl-2-ethylaminophenylimino)-3′-benzyl-3-(2-hydroxyethyl)-5-methyl-4-phenyl-2′,3′-dihydro-3H-[2,5′]bithiazolyliden-4′-one; N-[3-(3′-benzyl-3,5-dimethyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminophenyl]-2-methoxyacetamide; N-[3-(3′-benzyl-3,5-dimethyl-4′-oxo-4-phenyl-3′,4′-dihydro-3H-[2,5′]bithiazolyliden-2′-ylideneamino)-4-ethylaminophenyl]-2-dimethylaminoacetamide; 3-[3-cyclohexyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 3-[3-allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 3-allyl-5-(3-methyl-3H-benzothiazol-2-ylidene)-2-(quinolin-5-ylimino)thiazolidin-4-one; 3-allyl-2-(4-hydroxy-5-isopropyl-2-methylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-phenylthiazolidin-2-ylideneamino]benzonitrile; 3-cyclohexyl-2-(2-hydroxynaphthalen- 1-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-allyl-2-(2-hydroxynaphthalen-1-ylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)thiazolidin-4-one; 3-(4-cyclohexylphenylimino)-5-(3-methyl-3H-benzothiazol-2-ylidene)-3-phenylthiazolidin-4-one; 3-[3-benzyl-5-(6-fluoro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 3-[3-benzyl-5-(5-chloro-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 3-[3-benzyl-5-(6-ethoxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 4-ethylamino-3-[5-(3-methyl-3H-benzothiazol-2-ylidene)-4-oxo-3-propylthiazolidin-2-ylideneamino]benzonitrile; 3-[3-benzyl-5-(3-methyl-6-nitro-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; N-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}acetamide; 3-[3-benzyl-5-(6-hydroxy-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; ethylcarbamic acid 2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yl ester; {2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yloxy}acetic acid methyl ester; 2-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yloxy}acetamide; (2-chloroethyl)carbamic acid 2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yl ester; 3-{3-benzyl-5-[3-methyl-5-(2-methylaminoethoxy)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[5-(3-hydroxypropoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; (3-chloropropyl)carbamic acid 2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yl ester; 3-(3-benzyl-5-{3-methyl-5-[2-(4-methylpiperazin-1-yl)-ethoxy]-3H-benzothiazol-2-ylidene}-4-oxothiazolidin-2-ylideneamino)-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[3-methyl-5-(2-piperidin-4-ylethoxy)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[5-(2-dimethylaminoethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; {2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yloxy}acetic acid; 3-{3-benzyl-5-[6-(2-hydroxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[6-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[3-methyl-6-(2-morpholin-4-ylethoxy)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[5-(2-methoxyethoxy)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[3-methyl-4-methoxy-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[3-methyl-4-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[3-methyl-4-chloro-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[3-methyl-6-trifluoromethoxy-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-[3-benzyl-5-(3,5,6-trimethyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; 3-[3-benzyl-5-(3-methyl-5-acetamido-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; N-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-6-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yl}-2,2,2-trifluoroacetamide; 3-[5-(6-amino-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; N-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-N′,N″-di(tert-butoxycarbonyl)guanidine; 2-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-1,1,-dimethylurea; N-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yl}-2,2,2-trifluoroacetamide; 3-[5-(5-amino-3-methyl-3H-benzothiazol-2-ylidene)-4-oxothiazolidin-2-ylideneamino]-4-ethylaminobenzonitrile; {2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}carbamic acid ethyl ester; N-[2-(3-benzyl-2-{5-cyano-2-[ethyl-(2-morpholin-ylethylamino]phenylimino}-4-oxothiazilidin-5-ylidene)3-methyl-2,3-dihydrobenzothiazol-6-yl]-2,2,2-trifluoroacetamide; N-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-2,2,2-trifluoro-N-(2-morpholin-4ylethyl)acetamide; 3-{3-benzyl-5-[3-methyl-6-(2-morpholin-4-yl-ethylamino)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; 3-{3-benzyl-5-[3-methyl-6-(2-piperidin-1-yl-ethylamino)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; N-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-5-yl}-2,2,2-trifluoro-N-(2-morpholin-4ylethyl)acetamide; 3-{3-benzyl-5-[3-methyl-5-(2-morpholin-4-yl-ethylamino)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; N-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazolidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}guanidine; 3-{3-benzyl-5-[3-methyl-6-(4-trifluoromethylbenzylamino)-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-ethylaminobenzonitrile; N-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-N-(3-fluoropropyl)-2,2,2-trifluoroacetamide; N-{2-[3-benzyl-2-(5-cyano-2-ethylaminophenylimino)-4-oxothiazilidin-5-ylidene]-3-methyl-2,3-dihydrobenzothiazol-6-yl}-N-(3-cyanopropyl)-2,2,2-trifluoroacetamide; 3-{3-benzyl-5-[6-(3-cyanopropylamino)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-(ethylamino)benzonitrile; 3-{3-benzyl-5-[6-(3-hydroxypropylamino)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-(ethylamino)benzonitrile; and 3-{3-benzyl-5-[6-(2-methoxyethylamino)-3-methyl-3H-benzothiazol-2-ylidene]-4-oxothiazolidin-2-ylideneamino}-4-(ethylamino)benzonitrile.
 56. An article of manufacture, comprising packaging material, a compound formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, E and G are selected from (i) or (ii) as follows: (i) A and G are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium, substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³, or A and G together form substituted or unsubstituted alkylene, substituted or unsubstituted azaalkylene, substituted or unsubstituted oxaalkylene, substituted or unsubstituted thiaalkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted 1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene, or substituted or unsubstituted 2-aza-1,3-butadienylene;  D and E are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, halo and pseudohalo or D and E together form a bond; or (ii) A and D; or E and G; together form substituted or unsubstituted alkylene, substituted or unsubstituted azaalkylene, substituted or unsubstituted oxaalkylene, or substituted or unsubstituted thiaalkylene; and the others of A, D, E and G are selected as in (i); X¹ and X² are each independently selected from O, S, S(═O), S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ and R² are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium, substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; R³ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylium, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ and C(═J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl or C(═J)R¹³; J is O, S or NR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ and R¹⁶ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl and heteroaryliumalkyl moieties of A, D, E, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one or more substituents each independently selected from Q¹, where Q¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino, hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo, arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy where y is 1 or 2; or two Q¹ groups, which substitute the same atom, together form alkylene; and each Q¹ is independently unsubstituted or substituted with one or more substituents each independently selected from Q²; each Q² is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy where y is 1 or 2; or two Q² groups, which substitute the same atom, together form alkylene; each Q² is independently unsubstituted or substituted with one or more substituents each independently selected from alkyl, halo and pseudohalo; R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹ together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹; with the proviso that when R³ is substituted or unsubstituted heteroarylium then the heteroatom substituent is not alkyl or aryl; which is effective for modulating the activity of a nuclear receptor or for treatment, prevention or amelioration of one or more symptoms of nuclear receptor mediated diseases or disorders, or diseases or disorders in which nuclear receptor activity is implicated, within the packaging material, and a label that indicates that the compound or pharmaceutically acceptable derivative thereof is used for modulating the activity of a nuclear receptor or for treatment, prevention or amelioration of one or more symptoms of nuclear receptor mediated diseases or disorders, or diseases or disorders in which nuclear receptor activity is implicated.
 57. A method of treating, preventing, or ameliorating the symptoms of a disease or disorder that is modulated or otherwise affected by nuclear receptor activity or in which nuclear receptor activity is implicated, comprising administering to a subject in need thereof an effective amount of a compound formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, E and G are selected from (i) or (ii) as follows: (i) A and G are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium, substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³, or A and G together form substituted or unsubstituted alkylene, substituted or unsubstituted azaalkylene, substituted or unsubstituted oxaalkylene, substituted or unsubstituted thiaalkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted 1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene, or substituted or unsubstituted 2-aza-1,3-butadienylene;  D and E are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, halo and pseudohalo or D and E together form a bond; or (ii) A and D; or E and G; together form substituted or unsubstituted alkylene, substituted or unsubstituted azaalkylene, substituted or unsubstituted oxaalkylene, or substituted or unsubstituted thiaalkylene; and the others of A, D, E and G are selected as in (i); X¹ and X² are each independently selected from O, S, S(═O), S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ and R² are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium, substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; R³ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylium, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ and C(═J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl or C(═J)R¹³; J is O, S or NR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ and R¹⁶ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl and heteroaryliumalkyl moieties of A, D, E, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one or more substituents each independently selected from Q¹, where Q¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino, hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo, arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy where y is 1 or 2; or two Q¹ groups, which substitute the same atom, together form alkylene; and each Q¹ is independently unsubstituted or substituted with one or more substituents each independently selected from Q²; each Q² is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R¹⁵)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy where y is 1 or 2; or two Q² groups, which substitute the same atom, together form alkylene; each Q² is independently unsubstituted or substituted with one or more substituents each independently selected from alkyl, halo and pseudohalo; R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹ together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹.
 58. The method of claim 57, wherein the disease or disorder is selected from hypercholesterolemia, hyperlipoproteinemia, hypertriglyceridemia, lipodystrophy, hyperglycemia, diabetes mellitus, dyslipidemia, atherosclerosis, gallstone disease, acne vulgaris, acneiforn skin conditions, diabetes, Parkinson's disease, cancer, Alzheimer's disease, inflammation, immunological disorders, lipid disorders, obesity, conditions characterized by a perturbed epidermal barrier function, hyperlipidemia, cholestasis, peripheral occlusive disease, ischemic stroke, conditions of disturbed differentiation or excess proliferation of the epidermis or mucous membrane, and cardiovascular disorders.
 59. A method of treating, preventing, or ameliorating one or more symptoms of a disease or disorder which is affected by cholesterol, triglyceride, or bile acid levels, comprising administering to a subject in need thereof an effective amount of a compound formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, E and G are selected from (i) or (ii) as follows: (i) A and G are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium, substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³, or A and G together form substituted or unsubstituted alkylene, substituted or unsubstituted azaalkylene, substituted or unsubstituted oxaalkylene, substituted or unsubstituted thiaalkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted 1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene, or substituted or unsubstituted 2-aza-1,3-butadienylene;  D and E are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, halo and pseudohalo or D and E together form a bond; or (ii) A and D; or E and G; together form substituted or unsubstituted alkylene, substituted or unsubstituted azaalkylene, substituted or unsubstituted oxaalkylene, or substituted or unsubstituted thiaalkylene;  and the others of A, D, E and G are selected as in (i); X¹ and X² are each independently selected from O, S, S(═O), S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ and R² are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium, substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; R³ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylium, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ and C(═J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl or C(═J)R¹³; J is O, S or NR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ and R¹⁶ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl and heteroaryliumalkyl moieties of A, D, E, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one or more substituents each independently selected from Q¹, where Q¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino, hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo, arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy where y is 1 or 2; or two Q¹ groups, which substitute the same atom, together form alkylene; and each Q¹ is independently unsubstituted or substituted with one or more substituents each independently selected from Q²; each Q² is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy where y is 1 or 2; or two Q² groups, which substitute the same atom, together form alkylene; each Q² is independently unsubstituted or substituted with one or more substituents each independently selected from alkyl, halo and pseudohalo; R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹ together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl: R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹.
 60. A method of modulating nuclear receptor activity, comprising contacting the nuclear receptor with a compound formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, E and G are selected from (i) or (ii) as follows: (i) A and G are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium, substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³, or A and G together form substituted or unsubstituted alkylene, substituted or unsubstituted azaalkylene, substituted or unsubstituted oxaalkylene, substituted or unsubstituted thiaalkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted 1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene, or substituted or unsubstituted 2-aza-1,3-butadienylene;  D and E are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, halo and pseudohalo or D and E together form a bond; or (ii) A and D; or E and G; together form substituted or unsubstituted alkylene, substituted or unsubstituted azaalkylene, substituted or unsubstituted oxaalkylene, or substituted or unsubstituted thiaalkylene;  and the others of A, D, E and G are selected as in (i); X¹ and X² are each independently selected from O, S, S(═O), S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ and R² are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium, substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; R³ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylium, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ and C(═J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl or C(═J)R¹³; J is O, S or NR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ and R¹⁶ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl and heteroaryliumalkyl moieties of A, D, E, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one or more substituents each independently selected from Q¹, where Q¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino, hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo, arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy where y is 1 or 2; or two Q¹ groups, which substitute the same atom, together form alkylene; and each Q¹ is independently unsubstituted or substituted with one or more substituents each independently selected from Q²; each Q² is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy where y is 1 or 2; or two Q² groups, which substitute the same atom, together form alkylene; each Q² is independently unsubstituted or substituted with one or more substituents each independently selected from alkyl, halo and pseudohalo; R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹ together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹.
 61. A method of treating, preventing, or ameliorating one or more symptoms of cholestasis in a subject in need thereof, comprising administrating an effective amount of a compound of formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: A, D, E and G are selected from (i) or (ii) as follows: (i) A and G are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium, substituted or unsubstituted heteroaryliumalkyl, halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³, or A and G together form substituted or unsubstituted alkylene, substituted or unsubstituted azaalkylene, substituted or unsubstituted oxaalkylene, substituted or unsubstituted thiaalkylene, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, substituted or unsubstituted 1,3-butadienylene, substituted or unsubstituted 1-aza-1,3-butadienylene, or substituted or unsubstituted 2-aza-1,3-butadienylene;  D and E are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, halo and pseudohalo or D and E together form a bond; or (ii) A and D; or E and G; together form substituted or unsubstituted alkylene, substituted or unsubstituted azaalkylene, substituted or unsubstituted oxaalkylene, or substituted or unsubstituted thiaalkylene;  and the others of A, D, E and G are selected as in (i); X¹ and X² are each independently selected from O, S, S(═O), S(═O)₂, Se, NR⁵, CR⁶R⁷ and CR⁸═CR⁹; X³ is O, S, Se, NR⁵ or CR⁶R⁷; R¹ and R² are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroarylium, substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; R³is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylium, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted heteroaryliumalkyl, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹¹R¹² and C(═J)R¹³; where R⁵, R⁶, R⁷, R⁸ and R⁹ are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ and C(═J)R¹³; R¹⁰, R¹¹ and R¹² are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl or C(═J)R¹³; J is O, S or NR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ and R¹⁶ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl; where the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, heteroarylium, aralkyl, heteroaralkyl and heteroaryliumalkyl moieties of A, D, E, G, R¹, R², R³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹³ are unsubstituted or substituted with one or more substituents each independently selected from Q¹, where Q¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino, hydroxyimino, alkoxyimino, aryloxyimino, aralkoxyimino, alkylazo, arylazo, aralkylazo, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy where y is 1 or 2; or two Q¹ groups, which substitute the same atom, together form alkylene; and each Q¹ is independently unsubstituted or substituted with one or more substituents each independently selected from Q²; each Q² is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy where y is 1 or 2; or two Q² groups, which substitute the same atom, together form alkylene; each Q² is independently unsubstituted or substituted with one or more substituents each independently selected from alkyl, halo and pseudohalo; R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹ together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹.
 62. The compound of claim 1 that has formulae I:

or a pharmaceutically acceptable derivative thereof, wherein: X¹, X² and X³ are selected from (i) or (ii) as follows: (i) X¹, X² and X³ are each independently S, O or NR⁵; or (ii) X¹ is —CR⁸═CR⁹—, where R⁸ and R⁹ are each independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, NR¹⁴R¹⁵ and C(═J)R¹³, and X² and X³ are each independently S, O or NR⁵; R¹ is substituted or unsubstituted alkyl, where there are 0 to 6 substituents selected from alkoxy, alkoxyalkyl, hydroxycarbonyl, alkylcarbonyloxy, hydroxy, halo, pseudohalo, aryl and heteroaryl; R² is substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroaralkyl, or substituted or unsubstituted heterocyclylalkyl; where there are 0 or 1 substituents selected from alkoxycarbonyl and hydroxycarbonyl; R³ is substituted or unsubstituted heteroaryl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; where there are 0 to 5 substituents selected from alkylamino, cyano, cycloalkyl, hydroxy, alkoxy, dialkylamino, amino, heterocyclyl, aralkoxy, alkyl, nitro, haloalkyl, alkylcarbonyl, halo, alkylcarbonylamino, alkoxyalkylcarbonyl-amino, dialkylaminoalkylcarbonylamino, aminocarbonyl, alkoxycarbonyl, aralkylamino, cycloalkylamino, heterocyclylamino, haloalkylamino, haloalkoxy, hydroxycarbonyl, aminosulfonyl, alkylcarbonylaminosulfonyl, or haloalkylcarbonylamino, or any two substituents, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy; A and G are each independently selected from hydrogen, substituted or unsubstituted aryl, substituted or unsubstituted alkyl, substituted or unsubstituted alkoxycarbonyl, hydroxycarbonyl, and substituted or unsubstituted alkylcarbonyl, where there are 0 to 5 substituents selected from aryl, haloalkyl, haloalkoxy, nitro, halo, pseudohalo, hydroxy, alkyl and alkoxy, or A and G together form substituted or unsubstituted alkylene, or substituted or unsubstituted azaalkylene, where there are 0 to 4 substituents selected from halo, pseudohalo, alkoxy, nitro, haloalkyl, alkylcarbonylamino, hydroxy, alkylaminocarbonyloxy, alkoxycarbonylalkoxy, aminocarbonylalkoxy, hydroxyalkoxy, alkyl, haloalkylaminocarbonyloxy and alkylaminoalkoxy; D and E are each hydrogen, or together form a bond; and R⁵ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, halo, pseudohalo, OR¹⁰, SR¹⁰, S(═O)R¹³, S(═O)₂R¹³, NR¹⁴R¹⁵ or C(═J)R¹³; R¹⁰ is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl or C(═J)R¹³; J is O, S or NR¹⁴; R¹³ is selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted heterocyclylalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaralkyl, pseudohalo, OR¹⁶ and NR¹⁴R¹⁵; R¹⁴, R¹⁵ and R¹⁶ are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl and heteroaralkyl moieties of R⁵, R¹⁰ and R¹³ are unsubstituted or substituted with one or more substituents each independently selected from Q¹, where Q¹ is halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, imino, hydroxyimino, alkoxyimino, aralkoxyimino, arylazo, haloalkylcarbonylamino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R⁵⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q¹ groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy; or two Q¹ groups, which substitute the same atom, together form alkylene; each Q¹ is independently unsubstituted or substituted with one or more substituents each independently selected from Q²; each Q² is independently halo, pseudohalo, hydroxy, oxo, thia, nitrile, nitro, formyl, mercapto, hydroxycarbonyl, hydroxycarbonylalkyl, alkyl, haloalkyl, polyhaloalkyl, aminoalkyl, diaminoalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, heteroaryl, aralkyl, aralkenyl, aralkynyl, heteroarylalkyl, trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl, triarylsilyl, alkylidene, arylalkylidene, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, alkoxycarbonylalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, aralkoxycarbonyl, aralkoxycarbonylalkyl, arylcarbonylalkyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, heteroaryloxy, heteroaralkoxy, heterocyclyloxy, cycloalkoxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, aralkoxy, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, aralkoxycarbonyloxy, aminocarbonyloxy, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkylarylaminocarbonyloxy, diarylaminocarbonyloxy, guanidino, isothioureido, ureido, N-alkylureido, N-arylureido, N′-alkylureido, N′,N′-dialkylureido, N′-alkyl-N′-arylureido, N′,N′-diarylureido, N′-arylureido, N,N′-dialkylureido, N-alkyl-N′-arylureido, N-aryl-N′-alkylureido, N,N′-diarylureido, N,N′,N′-trialkylureido, N,N′-dialkyl-N′-arylureido, N-alkyl-N′,N′-diarylureido, N-aryl-N′,N′-dialkylureido, N,N′-diaryl-N′-alkylureido, N,N′,N′-triarylureido, amidino, alkylamidino, arylamidino, aminothiocarbonyl, alkylaminothiocarbonyl, arylaminothiocarbonyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylarylaminoalkyl, alkylamino, dialkylamino, haloalkylamino, arylamino, diarylamino, alkylarylamino, alkylcarbonylamino, alkoxycarbonylamino, aralkoxycarbonylamino, arylcarbonylamino, arylcarbonylaminoalkyl, aryloxycarbonylaminoalkyl, aryloxyarylcarbonylamino, aryloxycarbonylamino, alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, heterocyclylsulfonylamino, heteroarylthio, azido, —N⁺R⁵¹R⁵²R⁵³, P(R⁵⁰)₂, P(═O)(R¹⁰)₂, OP(═O)(R⁵⁰)₂, —NR⁶⁰C(═O)R⁶³, dialkylphosphonyl, alkylarylphosphonyl, diarylphosphonyl, hydroxyphosphonyl, alkylthio, arylthio, perfluoroalkylthio, hydroxycarbonylalkylthio, thiocyano, isothiocyano, alkylsulfinyloxy, alkylsulfonyloxy, arylsulfinyloxy, arylsulfonyloxy, hydroxysulfonyloxy, alkoxysulfonyloxy, aminosulfonyloxy, alkylaminosulfonyloxy, dialkylaminosulfonyloxy, arylaminosulfonyloxy, diarylaminosulfonyloxy, alkylarylaminosulfonyloxy, alkylsulfinyl, alkylsulfonyl, arylsulfinyl, arylsulfonyl, hydroxysulfonyl, alkoxysulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, arylaminosulfonyl, diarylaminosulfonyl or alkylarylaminosulfonyl; or two Q² groups, which substitute atoms in a 1,2 or 1,3 arrangement, together form alkylenedioxy, thioalkylenoxy or alkylenedithioxy where y is 1 or 2; or two Q² groups, which substitute the same atom, together form alkylene; R⁵⁰ is hydroxy, alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹, where R⁷⁰ and R⁷¹ are each independently hydrogen, alkyl, aralkyl, aryl, heteroaryl, heteroaralkyl or heterocyclyl, or R⁷⁰ and R⁷¹ together form alkylene, azaalkylene, oxaalkylene or thiaalkylene; R⁵¹, R⁵² and R⁵³ are each independently hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; R⁶⁰ is hydrogen, alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl; and R⁶³ is alkoxy, aralkoxy, alkyl, heteroaryl, heterocyclyl, aryl or —NR⁷⁰R⁷¹. 